Case Letter

To the Editor:

Nevus of Ota, also known as oculodermal melanocytosis or nevus fuscoceruleus ophthalmomaxillaris, is a hamartoma of dermal melanocytes that is characterized by a unilateral or bilateral blue-brown, speckled patch usually involving the malar, periorbital, temple, and/or forehead regions of the face.¹ It also may affect the sclera, conjunctiva, retinas, corneas, ocular muscles, periosteum, and retrobulbar fat corresponding to the distribution of the ophthalmic (V1) and maxillary (V2) divisions of the trigeminal nerve.

Examination of the oral cavity in the setting of nevus of Ota is imperative, as it can present as a developmental lesion of the oral mucosa.² Involvement of the hard palate is rare but has been observed.^3-5 We present a case of blue-pigmented macules in the upper right periorbital region with involvement of the hard palate that were diagnosed as nevus of Ota.

A 34-year-old Indian man presented with progressive, asymptomatic, ashy blue macules in the upper right periorbital region that had been present since birth. The pigmented macules had gradually increased to cover the infraorbital, maxillary, and temporal regions of the right side of the face with involvement of the conjunctiva and sclera (Figure 1).

Examination of the mucous membrane of the hard palate revealed several blue-pigmented macules with ill-defined borders merging into the surrounding mucosa (Figure 2). Ocular tension was normal and slit-lamp examination of the right eye did not reveal any abnormalities. Hematoxylin and eosin–stained sections prepared from a biopsy of the oral mucosa on the hard palate showed numerous elongated, fusiform, dendritic melanocytes in small aggregates scattered widely between the bundles of collagen in the papillary to midreticular dermis (Figure 3). On histology, the melanocytes stained positive for S100 protein (Figure 4) and human melanoma black 45. No evidence indicative of malignancy was found. The stratified squamous epithelium was unremarkable except for the presence of mild perivascular lymphocytic infiltrate in the subepithelial tissue. A diagnosis of nevus of Ota with involvement of the hard palate was made.

Cutaneous macules may enlarge slowly, become deeper in color, and persist throughout the patient’s life. Its pathogenesis is not known, but it is speculated that nevus of Ota is caused by faulty migration of melanoblasts from the neural crest to the skin. Nevus of Ito also is a dermal melanocytic aberration that exclusively affects the shoulders and often occurs in association with nevus of Ota.¹

Ashy or slate-blue pigmentation in individuals with skin of color (eg, Fitzpatrick skin type V) is uncommon, as this discoloration usually is seen in fair-skinned individuals (eg, Fitzpatrick skin type II).⁶ Occasionally, blue-pigmented lesions of the oral mucosa may be seen in nevus of Ota (as in our patient) and are considered developmental; therefore, examination of the oral cavity is suggested when patients present with blue-pigmented lesions in the facial region. Although this finding is rare, several other cases of blue-pigmented macules on the palatal mucosa have been reported.^3-5

The diagnosis of nevus of Ota should be confirmed by histopathology and can be classified into 5 types according to the distribution of melanocytes, including (1) superficial, (2) superficial dominant, (3) diffuse, (4) deep dominant, and (5) deep.⁷ The diagnosis of nevus of Ota can be made based on its characteristic morphology; however, nevus of 
Ito, Mongolian spots, melanoma, fixed drug eruptions,⁸ and lichen planus pigmantosus should also 
be ruled out.⁹

Nevus of Ota is a well-established entity that should be considered when ashy or slate-blue pigmentation is noted along the branches of the ophthalmic and maxillary divisions of the trigeminal nerve. Diagnosis is largely clinical, but should be confirmed on histopathology and immunohistochemistry. Possible concomitant involvement of the buccal mucosa and/or the hard palate warrants a thorough examination of the oral cavity in the setting of nevus of Ota to identify oral mucosal lesions. Histopathology is essential to confirm its status as well as to exclude melanoma.

To the Editor:

Nevus of Ota, also known as oculodermal melanocytosis or nevus fuscoceruleus ophthalmomaxillaris, is a hamartoma of dermal melanocytes that is characterized by a unilateral or bilateral blue-brown, speckled patch usually involving the malar, periorbital, temple, and/or forehead regions of the face.¹ It also may affect the sclera, conjunctiva, retinas, corneas, ocular muscles, periosteum, and retrobulbar fat corresponding to the distribution of the ophthalmic (V1) and maxillary (V2) divisions of the trigeminal nerve.

Examination of the oral cavity in the setting of nevus of Ota is imperative, as it can present as a developmental lesion of the oral mucosa.² Involvement of the hard palate is rare but has been observed.^3-5 We present a case of blue-pigmented macules in the upper right periorbital region with involvement of the hard palate that were diagnosed as nevus of Ota.

A 34-year-old Indian man presented with progressive, asymptomatic, ashy blue macules in the upper right periorbital region that had been present since birth. The pigmented macules had gradually increased to cover the infraorbital, maxillary, and temporal regions of the right side of the face with involvement of the conjunctiva and sclera (Figure 1).

Examination of the mucous membrane of the hard palate revealed several blue-pigmented macules with ill-defined borders merging into the surrounding mucosa (Figure 2). Ocular tension was normal and slit-lamp examination of the right eye did not reveal any abnormalities. Hematoxylin and eosin–stained sections prepared from a biopsy of the oral mucosa on the hard palate showed numerous elongated, fusiform, dendritic melanocytes in small aggregates scattered widely between the bundles of collagen in the papillary to midreticular dermis (Figure 3). On histology, the melanocytes stained positive for S100 protein (Figure 4) and human melanoma black 45. No evidence indicative of malignancy was found. The stratified squamous epithelium was unremarkable except for the presence of mild perivascular lymphocytic infiltrate in the subepithelial tissue. A diagnosis of nevus of Ota with involvement of the hard palate was made.

Cutaneous macules may enlarge slowly, become deeper in color, and persist throughout the patient’s life. Its pathogenesis is not known, but it is speculated that nevus of Ota is caused by faulty migration of melanoblasts from the neural crest to the skin. Nevus of Ito also is a dermal melanocytic aberration that exclusively affects the shoulders and often occurs in association with nevus of Ota.¹

Ashy or slate-blue pigmentation in individuals with skin of color (eg, Fitzpatrick skin type V) is uncommon, as this discoloration usually is seen in fair-skinned individuals (eg, Fitzpatrick skin type II).⁶ Occasionally, blue-pigmented lesions of the oral mucosa may be seen in nevus of Ota (as in our patient) and are considered developmental; therefore, examination of the oral cavity is suggested when patients present with blue-pigmented lesions in the facial region. Although this finding is rare, several other cases of blue-pigmented macules on the palatal mucosa have been reported.^3-5

The diagnosis of nevus of Ota should be confirmed by histopathology and can be classified into 5 types according to the distribution of melanocytes, including (1) superficial, (2) superficial dominant, (3) diffuse, (4) deep dominant, and (5) deep.⁷ The diagnosis of nevus of Ota can be made based on its characteristic morphology; however, nevus of 
Ito, Mongolian spots, melanoma, fixed drug eruptions,⁸ and lichen planus pigmantosus should also 
be ruled out.⁹

Nevus of Ota is a well-established entity that should be considered when ashy or slate-blue pigmentation is noted along the branches of the ophthalmic and maxillary divisions of the trigeminal nerve. Diagnosis is largely clinical, but should be confirmed on histopathology and immunohistochemistry. Possible concomitant involvement of the buccal mucosa and/or the hard palate warrants a thorough examination of the oral cavity in the setting of nevus of Ota to identify oral mucosal lesions. Histopathology is essential to confirm its status as well as to exclude melanoma.

To the Editor:

Nevus of Ota, also known as oculodermal melanocytosis or nevus fuscoceruleus ophthalmomaxillaris, is a hamartoma of dermal melanocytes that is characterized by a unilateral or bilateral blue-brown, speckled patch usually involving the malar, periorbital, temple, and/or forehead regions of the face.¹ It also may affect the sclera, conjunctiva, retinas, corneas, ocular muscles, periosteum, and retrobulbar fat corresponding to the distribution of the ophthalmic (V1) and maxillary (V2) divisions of the trigeminal nerve.

Examination of the oral cavity in the setting of nevus of Ota is imperative, as it can present as a developmental lesion of the oral mucosa.² Involvement of the hard palate is rare but has been observed.^3-5 We present a case of blue-pigmented macules in the upper right periorbital region with involvement of the hard palate that were diagnosed as nevus of Ota.

A 34-year-old Indian man presented with progressive, asymptomatic, ashy blue macules in the upper right periorbital region that had been present since birth. The pigmented macules had gradually increased to cover the infraorbital, maxillary, and temporal regions of the right side of the face with involvement of the conjunctiva and sclera (Figure 1).

Examination of the mucous membrane of the hard palate revealed several blue-pigmented macules with ill-defined borders merging into the surrounding mucosa (Figure 2). Ocular tension was normal and slit-lamp examination of the right eye did not reveal any abnormalities. Hematoxylin and eosin–stained sections prepared from a biopsy of the oral mucosa on the hard palate showed numerous elongated, fusiform, dendritic melanocytes in small aggregates scattered widely between the bundles of collagen in the papillary to midreticular dermis (Figure 3). On histology, the melanocytes stained positive for S100 protein (Figure 4) and human melanoma black 45. No evidence indicative of malignancy was found. The stratified squamous epithelium was unremarkable except for the presence of mild perivascular lymphocytic infiltrate in the subepithelial tissue. A diagnosis of nevus of Ota with involvement of the hard palate was made.

Cutaneous macules may enlarge slowly, become deeper in color, and persist throughout the patient’s life. Its pathogenesis is not known, but it is speculated that nevus of Ota is caused by faulty migration of melanoblasts from the neural crest to the skin. Nevus of Ito also is a dermal melanocytic aberration that exclusively affects the shoulders and often occurs in association with nevus of Ota.¹

Ashy or slate-blue pigmentation in individuals with skin of color (eg, Fitzpatrick skin type V) is uncommon, as this discoloration usually is seen in fair-skinned individuals (eg, Fitzpatrick skin type II).⁶ Occasionally, blue-pigmented lesions of the oral mucosa may be seen in nevus of Ota (as in our patient) and are considered developmental; therefore, examination of the oral cavity is suggested when patients present with blue-pigmented lesions in the facial region. Although this finding is rare, several other cases of blue-pigmented macules on the palatal mucosa have been reported.^3-5

The diagnosis of nevus of Ota should be confirmed by histopathology and can be classified into 5 types according to the distribution of melanocytes, including (1) superficial, (2) superficial dominant, (3) diffuse, (4) deep dominant, and (5) deep.⁷ The diagnosis of nevus of Ota can be made based on its characteristic morphology; however, nevus of 
Ito, Mongolian spots, melanoma, fixed drug eruptions,⁸ and lichen planus pigmantosus should also 
be ruled out.⁹

Nevus of Ota is a well-established entity that should be considered when ashy or slate-blue pigmentation is noted along the branches of the ophthalmic and maxillary divisions of the trigeminal nerve. Diagnosis is largely clinical, but should be confirmed on histopathology and immunohistochemistry. Possible concomitant involvement of the buccal mucosa and/or the hard palate warrants a thorough examination of the oral cavity in the setting of nevus of Ota to identify oral mucosal lesions. Histopathology is essential to confirm its status as well as to exclude melanoma.

To the Editor:

Contact sensitivity to drugs that are systemically administered can occur among health care workers.¹ We report the case of a 28-year-old nurse who developed eczema on the dorsal aspect of the hand (Figure 1A) and the face (Figure 1B) in the workplace. The nurse was working in the hematology department where she usually handled and administered antibiotics such as imipenem, ertapenem, piperacillin, vancomycin, anidulafungin, teicoplanin, and ciprofloxacin. She was moved to a different department where she did not have contact with the suspicious drugs and the dermatitis completely resolved.

One month after the resolution of the eczema she was referred to our allergy department for an allergological evaluation. A dermatologic evaluation was made and a skin biopsy was performed from a lesional area of the left hand. The patient underwent delayed skin test and patch tests with many β-lactam compounds including penicilloyl polylysine, minor determinant mixture, penicillin G, penicillin V, ampicillin, amoxicillin, bacampicillin, piperacillin, mezlocillin and ticarcillin, imipenem-cilastatin, aztreonam, meropenem, ertapenem, and cephalosporins (eg, cephalexin, cefaclor, cefalotin, cefadroxil, cephradine, cefuroxime, ceftriaxone, cefixime, cefoperazone, cefamandole, ceftazidime, cefotaxime). Undiluted solutions of commercial drugs (parenteral drugs when available were used) were used for skin prick test, and if negative, they were tested intradermally as described by Schiavino et al.² The concentrations used for the skin test and for the patch test are reported in the Table. Histamine (10 mg/mL) and saline were employed as positive and negative controls, respectively. Immediate reactions of at least 3 mm greater in diameter compared to the control for the skin prick test and 5 mm greater for intradermal tests were considered positive. Immediate-type skin tests were read after 20 minutes and also after 48 hours should any delayed reaction occur. An infiltrated erythema with a diameter greater than 5 mm was considered a delayed positive reaction.

Patch tests were applied to the interscapular region using acrylate adhesive strips with small plates. They were evaluated at 48 and 72 hours. Positivity was assessed according to the indications of the European Network for Drug Allergy.³ Patch tests were carried out using the same drugs as the skin test. All drugs were mixed in petrolatum at 
25% wt/wt for ampicillin and amoxicillin, 5% for penicillin G, and 20% for the other drugs as recommended by Schiavino et al.² We also performed patch tests with ertapenem in 20 healthy controls.

A skin biopsy from lesional skin showed a perivascular infiltrate of the upper dermis with spongiosis of the lesional area similar to eczema. Patch tests and intradermal tests were positive for ertapenem after 48 hours (Figure 2). Imipenem-cilastatin, ampicillin, piperacillin, mezlocillin, and meropenem showed a positive reaction for patch tests. We concluded that the patient had delayed hypersensitivity to carbapenems (ertapenem, imipenem-cilastatin, and meropenem) and semisynthetic penicillins (piperacillin, mezlocillin, and ampicillin).

Drug sensitization in nurses and in health care workers can occur. Natural and semisynthetic penicillin can cause allergic contact dermatitis in health care workers. We report a case of occupational allergy to ertapenem, which is a 1-β-methyl-carbapenem that is administered as a single agent. It is highly active in vitro against bacteria that are generally associated with community-acquired and mixed aerobic and anaerobic infections.⁴ Occupational contact allergy to other carbapenems such as meropenem also was reported.⁵ The contact sensitization potential of imipenem has been confirmed in the guinea pig.⁶ Carbapenems have a bicyclic nucleus composed by a β-lactam ring with an associated 5-membered ring. In our patient, patch tests for ertapenem, imipenem, and meropenem were positive. Although the cross-reactivity between imipenem and penicillin has been demonstrated,² data on the cross-reactivity between the carbapenems are not strong. Bauer et al⁷ reported a case of an allergy to imipenem-cilastatin that tolerated treatment with meropenem, but our case showed a complete cross-reactivity between carbapenems. Patch tests for ampicillin, mezlocillin, and piperacillin also were positive; therefore, it can be hypothesized that in our patient, the β-lactam ring was the main epitope recognized by T lymphocytes. Gielen and Goossens¹ reported in a study on work-related dermatitis that the most common sensitizers were antibiotics such as penicillins, cephalosporins, and aminoglycosides.

Health care workers should protect their hands with gloves during the preparation of drugs because they have the risk for developing an occupational contact allergy. Detailed allergological and dermatological evaluation is mandatory to confirm or exclude occupational contact allergy.

To the Editor:

Contact sensitivity to drugs that are systemically administered can occur among health care workers.¹ We report the case of a 28-year-old nurse who developed eczema on the dorsal aspect of the hand (Figure 1A) and the face (Figure 1B) in the workplace. The nurse was working in the hematology department where she usually handled and administered antibiotics such as imipenem, ertapenem, piperacillin, vancomycin, anidulafungin, teicoplanin, and ciprofloxacin. She was moved to a different department where she did not have contact with the suspicious drugs and the dermatitis completely resolved.

One month after the resolution of the eczema she was referred to our allergy department for an allergological evaluation. A dermatologic evaluation was made and a skin biopsy was performed from a lesional area of the left hand. The patient underwent delayed skin test and patch tests with many β-lactam compounds including penicilloyl polylysine, minor determinant mixture, penicillin G, penicillin V, ampicillin, amoxicillin, bacampicillin, piperacillin, mezlocillin and ticarcillin, imipenem-cilastatin, aztreonam, meropenem, ertapenem, and cephalosporins (eg, cephalexin, cefaclor, cefalotin, cefadroxil, cephradine, cefuroxime, ceftriaxone, cefixime, cefoperazone, cefamandole, ceftazidime, cefotaxime). Undiluted solutions of commercial drugs (parenteral drugs when available were used) were used for skin prick test, and if negative, they were tested intradermally as described by Schiavino et al.² The concentrations used for the skin test and for the patch test are reported in the Table. Histamine (10 mg/mL) and saline were employed as positive and negative controls, respectively. Immediate reactions of at least 3 mm greater in diameter compared to the control for the skin prick test and 5 mm greater for intradermal tests were considered positive. Immediate-type skin tests were read after 20 minutes and also after 48 hours should any delayed reaction occur. An infiltrated erythema with a diameter greater than 5 mm was considered a delayed positive reaction.

Patch tests were applied to the interscapular region using acrylate adhesive strips with small plates. They were evaluated at 48 and 72 hours. Positivity was assessed according to the indications of the European Network for Drug Allergy.³ Patch tests were carried out using the same drugs as the skin test. All drugs were mixed in petrolatum at 
25% wt/wt for ampicillin and amoxicillin, 5% for penicillin G, and 20% for the other drugs as recommended by Schiavino et al.² We also performed patch tests with ertapenem in 20 healthy controls.

A skin biopsy from lesional skin showed a perivascular infiltrate of the upper dermis with spongiosis of the lesional area similar to eczema. Patch tests and intradermal tests were positive for ertapenem after 48 hours (Figure 2). Imipenem-cilastatin, ampicillin, piperacillin, mezlocillin, and meropenem showed a positive reaction for patch tests. We concluded that the patient had delayed hypersensitivity to carbapenems (ertapenem, imipenem-cilastatin, and meropenem) and semisynthetic penicillins (piperacillin, mezlocillin, and ampicillin).

Drug sensitization in nurses and in health care workers can occur. Natural and semisynthetic penicillin can cause allergic contact dermatitis in health care workers. We report a case of occupational allergy to ertapenem, which is a 1-β-methyl-carbapenem that is administered as a single agent. It is highly active in vitro against bacteria that are generally associated with community-acquired and mixed aerobic and anaerobic infections.⁴ Occupational contact allergy to other carbapenems such as meropenem also was reported.⁵ The contact sensitization potential of imipenem has been confirmed in the guinea pig.⁶ Carbapenems have a bicyclic nucleus composed by a β-lactam ring with an associated 5-membered ring. In our patient, patch tests for ertapenem, imipenem, and meropenem were positive. Although the cross-reactivity between imipenem and penicillin has been demonstrated,² data on the cross-reactivity between the carbapenems are not strong. Bauer et al⁷ reported a case of an allergy to imipenem-cilastatin that tolerated treatment with meropenem, but our case showed a complete cross-reactivity between carbapenems. Patch tests for ampicillin, mezlocillin, and piperacillin also were positive; therefore, it can be hypothesized that in our patient, the β-lactam ring was the main epitope recognized by T lymphocytes. Gielen and Goossens¹ reported in a study on work-related dermatitis that the most common sensitizers were antibiotics such as penicillins, cephalosporins, and aminoglycosides.

Health care workers should protect their hands with gloves during the preparation of drugs because they have the risk for developing an occupational contact allergy. Detailed allergological and dermatological evaluation is mandatory to confirm or exclude occupational contact allergy.

To the Editor:

Contact sensitivity to drugs that are systemically administered can occur among health care workers.¹ We report the case of a 28-year-old nurse who developed eczema on the dorsal aspect of the hand (Figure 1A) and the face (Figure 1B) in the workplace. The nurse was working in the hematology department where she usually handled and administered antibiotics such as imipenem, ertapenem, piperacillin, vancomycin, anidulafungin, teicoplanin, and ciprofloxacin. She was moved to a different department where she did not have contact with the suspicious drugs and the dermatitis completely resolved.

One month after the resolution of the eczema she was referred to our allergy department for an allergological evaluation. A dermatologic evaluation was made and a skin biopsy was performed from a lesional area of the left hand. The patient underwent delayed skin test and patch tests with many β-lactam compounds including penicilloyl polylysine, minor determinant mixture, penicillin G, penicillin V, ampicillin, amoxicillin, bacampicillin, piperacillin, mezlocillin and ticarcillin, imipenem-cilastatin, aztreonam, meropenem, ertapenem, and cephalosporins (eg, cephalexin, cefaclor, cefalotin, cefadroxil, cephradine, cefuroxime, ceftriaxone, cefixime, cefoperazone, cefamandole, ceftazidime, cefotaxime). Undiluted solutions of commercial drugs (parenteral drugs when available were used) were used for skin prick test, and if negative, they were tested intradermally as described by Schiavino et al.² The concentrations used for the skin test and for the patch test are reported in the Table. Histamine (10 mg/mL) and saline were employed as positive and negative controls, respectively. Immediate reactions of at least 3 mm greater in diameter compared to the control for the skin prick test and 5 mm greater for intradermal tests were considered positive. Immediate-type skin tests were read after 20 minutes and also after 48 hours should any delayed reaction occur. An infiltrated erythema with a diameter greater than 5 mm was considered a delayed positive reaction.

Patch tests were applied to the interscapular region using acrylate adhesive strips with small plates. They were evaluated at 48 and 72 hours. Positivity was assessed according to the indications of the European Network for Drug Allergy.³ Patch tests were carried out using the same drugs as the skin test. All drugs were mixed in petrolatum at 
25% wt/wt for ampicillin and amoxicillin, 5% for penicillin G, and 20% for the other drugs as recommended by Schiavino et al.² We also performed patch tests with ertapenem in 20 healthy controls.

A skin biopsy from lesional skin showed a perivascular infiltrate of the upper dermis with spongiosis of the lesional area similar to eczema. Patch tests and intradermal tests were positive for ertapenem after 48 hours (Figure 2). Imipenem-cilastatin, ampicillin, piperacillin, mezlocillin, and meropenem showed a positive reaction for patch tests. We concluded that the patient had delayed hypersensitivity to carbapenems (ertapenem, imipenem-cilastatin, and meropenem) and semisynthetic penicillins (piperacillin, mezlocillin, and ampicillin).

Drug sensitization in nurses and in health care workers can occur. Natural and semisynthetic penicillin can cause allergic contact dermatitis in health care workers. We report a case of occupational allergy to ertapenem, which is a 1-β-methyl-carbapenem that is administered as a single agent. It is highly active in vitro against bacteria that are generally associated with community-acquired and mixed aerobic and anaerobic infections.⁴ Occupational contact allergy to other carbapenems such as meropenem also was reported.⁵ The contact sensitization potential of imipenem has been confirmed in the guinea pig.⁶ Carbapenems have a bicyclic nucleus composed by a β-lactam ring with an associated 5-membered ring. In our patient, patch tests for ertapenem, imipenem, and meropenem were positive. Although the cross-reactivity between imipenem and penicillin has been demonstrated,² data on the cross-reactivity between the carbapenems are not strong. Bauer et al⁷ reported a case of an allergy to imipenem-cilastatin that tolerated treatment with meropenem, but our case showed a complete cross-reactivity between carbapenems. Patch tests for ampicillin, mezlocillin, and piperacillin also were positive; therefore, it can be hypothesized that in our patient, the β-lactam ring was the main epitope recognized by T lymphocytes. Gielen and Goossens¹ reported in a study on work-related dermatitis that the most common sensitizers were antibiotics such as penicillins, cephalosporins, and aminoglycosides.

Health care workers should protect their hands with gloves during the preparation of drugs because they have the risk for developing an occupational contact allergy. Detailed allergological and dermatological evaluation is mandatory to confirm or exclude occupational contact allergy.

To the Editor:

A 52-year-old man presented to the emergency department with skin pain. Although he felt well overall, he reported that he had developed skin sores 3 weeks prior to presentation that were progressively causing skin pain and sleep loss. He acknowledged smoking cigarettes and snorting cocaine but denied intravenous use of cocaine or using any other drugs. His usual medications were lisinopril and tramadol, and he had no known drug allergies. His history was remarkable for methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis of the shoulder and MRSA prepatellar bursitis within the last 2 years. During examination in the emergency department he was alert, afebrile, nontoxic, generally healthy, and in no acute distress. Extensive necrotic skin lesions were present on the trunk, extremities, and both ears. The lesions were large necrotic patches with irregular, sharply angulated borders with thin or ulcerated epidermis surrounded by a bright halo of erythema (Figure 1). Ulcers were noted on the tongue (Figure 2).

Figure 1. Extensive skin necrosis on the leg from levamisole-contaminated cocaine (A). Necrotic skin lesions also were present on the trunk, arm (B), and ear (C).

Figure 2. Ulcers were noted on the tongue.

The clinical diagnosis was probable thrombosis of skin vessels with skin necrosis due to cocaine that was likely contaminated with levamisole. Pertinent laboratory results included the following: mild anemia and mild leukopenia; values within reference range for liver function, serum protein electrophoresis, hepatitis profile, human immunodeficiency virus 1 and 2, rapid plasma reagin, and antinuclear antibody; normal thrombotic studies for antithrombin III, protein C, protein S, factor V Leiden, prothrombin mutation G20210A, anticardiolipin IgG, IgM, and IgA; erythrocyte sedimentation rate of 
26 mm/h (reference range, 0–15 mm/h); perinuclear antineutrophil cytoplasmic antibody greater than 1:320 (reference range, <1:20) with normal proteinase 3 
and myeloperoxidase antibodies; urine positive for cocaine but blood negative for cocaine; normal chest radiograph; and normal electrocardiogram.

The patient was stable with good family support and was discharged from the emergency department to be followed in our dermatology office. The following day his skin biopsies were interpreted as neutrophilic vasculitis with extensive intravascular early and organizing thrombi involving all small- and medium-sized blood vessels consistent with levamisole-induced necrosis or septic vasculitis (Figure 3). With his history of MRSA septic arthritis and bursitis, he was hospitalized for treatment with intravenous vancomycin pending further studies. Skin biopsy for direct immunofluorescence revealed granular deposits of IgM and linear deposits of C3 at the dermoepidermal junction and in blood vessel walls. Two tissue cultures for bacteria and fungi were negative and 2 blood cultures were negative. An echocardiogram was normal and without evidence of emboli. The patient remained stable and antibiotics were discontinued. He was released from the hospital and his skin lesions healed satisfactorily with showering and mupirocin ointment.

Figure 3. Thrombotic occlusion of blood vessels was seen on histopathology (A and B)(H&E, original magnifications ×100 and ×400).

Cocaine is a white powder that is primarily derived from the leaves of the coca plant in South America. It is ingested orally; injected intravenously; snorted intranasally; chewed; eaten; used as a suppository; or dissolved in water and baking soda then heated to crystallization for smoking, which is the most addictive method and known as freebasing. When smoked, crack cocaine produces a crackling sound. Cocaine stimulates the central nervous system similar to amphetamine but may harm any body organ through vasoconstriction/vasospasm and cause skin necrosis without any additive. Perhaps less known is its ability to produce smooth muscle hyperplasia of small vessels and premature atherosclerosis.¹

Levamisole has been used to treat worms, cancer, and stimulation of the immune system but currently is used only by veterinarians because of agranulocytosis and vasculitis in humans. As of July 2009, the Drug Enforcement Agency reported that 69% of seized cocaine lots coming into the United States contained levamisole.² By January 2010, 73.2% of seized cocaine exhibits contained levamisole according to the California Poison Control System, with reports of contamination rates from across the country ranging from 40% to 90%.³ Levamisole is an inexpensive additive to cocaine and may increase the release of brain dopamine.⁴ It is difficult to detect levamisole in urine due to its short half-life of 
5.6 hours and only 2% to 5% of the parent compound being found in the urine.⁵

Skin necrosis due to cocaine-contaminated levamisole usually occurs in younger individuals who have characteristic skin lesions and a history of cocaine use. Skin lesions usually are multiple, purpuric or necrotic with irregular angulated edges and a halo of erythema. Ear involvement is common but not invariable.⁶ Descriptive adjectives include branched, netlike, retiform, and stellate, all revealing the compromised underlying dermal and subcutaneous vascular anatomy. Supportive evidence includes a decreased white blood cell count (neutropenia in up to 50%),⁵ positive antineutrophilic cytoplasmic antibodies,^5,7 and/or positive drug screen. Skin biopsy may reveal thrombosis,⁴ fibrin thrombi without vasculitis,⁸ or leukocytoclastic vasculitis,^4,5 or may suggest septic vasculitis.⁹ Direct immunofluorescence may suggest an immune complex-mediated vasculitis.⁵

The differential diagnosis for a patient with 
purpuric/necrotic skin lesions should be broad and include vasculitis (eg, inflammatory, antineutrophil cytoplasmic antibody positive, septic), hypercoagulopathy (eg, antiphospholipid syndrome, antithrombin III, prothrombin mutation G20210A, 
factor V Leiden, protein C, protein S), drugs 
(eg, heparin, warfarin, cocaine with or without levamisole, intravenous drug use, hydroxyurea, ergotamine, propylthiouracil¹⁰), calciphylaxis, 
cold-induced thrombosis, emboli (eg, atheroma, cholesterol, endocarditis, myxoma, aortic angiosarcoma, marantic), febrile ulceronecrotic Mucha-Habermann disease, infection especially if immunosuppressed (eg, disseminated Acanthamoeba/Candida/histoplasmosis/strongyloides/varicella-zoster virus, 
S aureus, streptococcus, ecthyma gangrenosum, gas gangrene, hemorrhagic smallpox, lues maligna with human immunodeficiency virus, Meleney ulcer, Rocky Mountain spotted fever, Vibrio vulnificus), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombocythemia, Waldenström hyperglobulinemic purpura, pyoderma gangrenosum, cancer (eg, paraneoplastic arterial thrombi), oxalosis, paraproteinemia (eg, multiple myeloma), and lupus with generalized coagulopathy. Less likely diagnoses might include Degos disease, factitial dermatitis, foreign bodies, multiple spider bites, paroxysmal nocturnal hemoglobinuria, sickle cell anemia, Buruli ulcer, or thromboangiitis obliterans. Branched, angulated, retiform lesions are an important finding, and some of these diagnostic possibilities are not classically retiform. However, clinical findings are not always classical, and astute physicians want to be circumspect. Had more ominous findings been present in our patient (eg, fever, hemodynamic instability, progressive skin lesions, systemic organ involvement), prompt hospitalization and additional considerations would have been necessary, such as septicemia (eg, meningococcemia, bubonic plague [Black Death], necrotizing 
fasciitis, purpura fulminans), catastrophic antiphospholipid syndrome, or disseminated intra-
vascular coagulation.

The prognosis for skin necrosis caused by 
levamisole-contaminated cocaine generally is good without long-term sequelae.⁵ Autoantibody 
serologies normalize within weeks to months after stopping levamisole.^5,8 Our patient recovered with conservative measures.

To the Editor:

A 52-year-old man presented to the emergency department with skin pain. Although he felt well overall, he reported that he had developed skin sores 3 weeks prior to presentation that were progressively causing skin pain and sleep loss. He acknowledged smoking cigarettes and snorting cocaine but denied intravenous use of cocaine or using any other drugs. His usual medications were lisinopril and tramadol, and he had no known drug allergies. His history was remarkable for methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis of the shoulder and MRSA prepatellar bursitis within the last 2 years. During examination in the emergency department he was alert, afebrile, nontoxic, generally healthy, and in no acute distress. Extensive necrotic skin lesions were present on the trunk, extremities, and both ears. The lesions were large necrotic patches with irregular, sharply angulated borders with thin or ulcerated epidermis surrounded by a bright halo of erythema (Figure 1). Ulcers were noted on the tongue (Figure 2).

Figure 1. Extensive skin necrosis on the leg from levamisole-contaminated cocaine (A). Necrotic skin lesions also were present on the trunk, arm (B), and ear (C).

Figure 2. Ulcers were noted on the tongue.

The clinical diagnosis was probable thrombosis of skin vessels with skin necrosis due to cocaine that was likely contaminated with levamisole. Pertinent laboratory results included the following: mild anemia and mild leukopenia; values within reference range for liver function, serum protein electrophoresis, hepatitis profile, human immunodeficiency virus 1 and 2, rapid plasma reagin, and antinuclear antibody; normal thrombotic studies for antithrombin III, protein C, protein S, factor V Leiden, prothrombin mutation G20210A, anticardiolipin IgG, IgM, and IgA; erythrocyte sedimentation rate of 
26 mm/h (reference range, 0–15 mm/h); perinuclear antineutrophil cytoplasmic antibody greater than 1:320 (reference range, <1:20) with normal proteinase 3 
and myeloperoxidase antibodies; urine positive for cocaine but blood negative for cocaine; normal chest radiograph; and normal electrocardiogram.

The patient was stable with good family support and was discharged from the emergency department to be followed in our dermatology office. The following day his skin biopsies were interpreted as neutrophilic vasculitis with extensive intravascular early and organizing thrombi involving all small- and medium-sized blood vessels consistent with levamisole-induced necrosis or septic vasculitis (Figure 3). With his history of MRSA septic arthritis and bursitis, he was hospitalized for treatment with intravenous vancomycin pending further studies. Skin biopsy for direct immunofluorescence revealed granular deposits of IgM and linear deposits of C3 at the dermoepidermal junction and in blood vessel walls. Two tissue cultures for bacteria and fungi were negative and 2 blood cultures were negative. An echocardiogram was normal and without evidence of emboli. The patient remained stable and antibiotics were discontinued. He was released from the hospital and his skin lesions healed satisfactorily with showering and mupirocin ointment.

Figure 3. Thrombotic occlusion of blood vessels was seen on histopathology (A and B)(H&E, original magnifications ×100 and ×400).

Cocaine is a white powder that is primarily derived from the leaves of the coca plant in South America. It is ingested orally; injected intravenously; snorted intranasally; chewed; eaten; used as a suppository; or dissolved in water and baking soda then heated to crystallization for smoking, which is the most addictive method and known as freebasing. When smoked, crack cocaine produces a crackling sound. Cocaine stimulates the central nervous system similar to amphetamine but may harm any body organ through vasoconstriction/vasospasm and cause skin necrosis without any additive. Perhaps less known is its ability to produce smooth muscle hyperplasia of small vessels and premature atherosclerosis.¹

Levamisole has been used to treat worms, cancer, and stimulation of the immune system but currently is used only by veterinarians because of agranulocytosis and vasculitis in humans. As of July 2009, the Drug Enforcement Agency reported that 69% of seized cocaine lots coming into the United States contained levamisole.² By January 2010, 73.2% of seized cocaine exhibits contained levamisole according to the California Poison Control System, with reports of contamination rates from across the country ranging from 40% to 90%.³ Levamisole is an inexpensive additive to cocaine and may increase the release of brain dopamine.⁴ It is difficult to detect levamisole in urine due to its short half-life of 
5.6 hours and only 2% to 5% of the parent compound being found in the urine.⁵

Skin necrosis due to cocaine-contaminated levamisole usually occurs in younger individuals who have characteristic skin lesions and a history of cocaine use. Skin lesions usually are multiple, purpuric or necrotic with irregular angulated edges and a halo of erythema. Ear involvement is common but not invariable.⁶ Descriptive adjectives include branched, netlike, retiform, and stellate, all revealing the compromised underlying dermal and subcutaneous vascular anatomy. Supportive evidence includes a decreased white blood cell count (neutropenia in up to 50%),⁵ positive antineutrophilic cytoplasmic antibodies,^5,7 and/or positive drug screen. Skin biopsy may reveal thrombosis,⁴ fibrin thrombi without vasculitis,⁸ or leukocytoclastic vasculitis,^4,5 or may suggest septic vasculitis.⁹ Direct immunofluorescence may suggest an immune complex-mediated vasculitis.⁵

The differential diagnosis for a patient with 
purpuric/necrotic skin lesions should be broad and include vasculitis (eg, inflammatory, antineutrophil cytoplasmic antibody positive, septic), hypercoagulopathy (eg, antiphospholipid syndrome, antithrombin III, prothrombin mutation G20210A, 
factor V Leiden, protein C, protein S), drugs 
(eg, heparin, warfarin, cocaine with or without levamisole, intravenous drug use, hydroxyurea, ergotamine, propylthiouracil¹⁰), calciphylaxis, 
cold-induced thrombosis, emboli (eg, atheroma, cholesterol, endocarditis, myxoma, aortic angiosarcoma, marantic), febrile ulceronecrotic Mucha-Habermann disease, infection especially if immunosuppressed (eg, disseminated Acanthamoeba/Candida/histoplasmosis/strongyloides/varicella-zoster virus, 
S aureus, streptococcus, ecthyma gangrenosum, gas gangrene, hemorrhagic smallpox, lues maligna with human immunodeficiency virus, Meleney ulcer, Rocky Mountain spotted fever, Vibrio vulnificus), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombocythemia, Waldenström hyperglobulinemic purpura, pyoderma gangrenosum, cancer (eg, paraneoplastic arterial thrombi), oxalosis, paraproteinemia (eg, multiple myeloma), and lupus with generalized coagulopathy. Less likely diagnoses might include Degos disease, factitial dermatitis, foreign bodies, multiple spider bites, paroxysmal nocturnal hemoglobinuria, sickle cell anemia, Buruli ulcer, or thromboangiitis obliterans. Branched, angulated, retiform lesions are an important finding, and some of these diagnostic possibilities are not classically retiform. However, clinical findings are not always classical, and astute physicians want to be circumspect. Had more ominous findings been present in our patient (eg, fever, hemodynamic instability, progressive skin lesions, systemic organ involvement), prompt hospitalization and additional considerations would have been necessary, such as septicemia (eg, meningococcemia, bubonic plague [Black Death], necrotizing 
fasciitis, purpura fulminans), catastrophic antiphospholipid syndrome, or disseminated intra-
vascular coagulation.

The prognosis for skin necrosis caused by 
levamisole-contaminated cocaine generally is good without long-term sequelae.⁵ Autoantibody 
serologies normalize within weeks to months after stopping levamisole.^5,8 Our patient recovered with conservative measures.

To the Editor:

A 52-year-old man presented to the emergency department with skin pain. Although he felt well overall, he reported that he had developed skin sores 3 weeks prior to presentation that were progressively causing skin pain and sleep loss. He acknowledged smoking cigarettes and snorting cocaine but denied intravenous use of cocaine or using any other drugs. His usual medications were lisinopril and tramadol, and he had no known drug allergies. His history was remarkable for methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis of the shoulder and MRSA prepatellar bursitis within the last 2 years. During examination in the emergency department he was alert, afebrile, nontoxic, generally healthy, and in no acute distress. Extensive necrotic skin lesions were present on the trunk, extremities, and both ears. The lesions were large necrotic patches with irregular, sharply angulated borders with thin or ulcerated epidermis surrounded by a bright halo of erythema (Figure 1). Ulcers were noted on the tongue (Figure 2).

Figure 1. Extensive skin necrosis on the leg from levamisole-contaminated cocaine (A). Necrotic skin lesions also were present on the trunk, arm (B), and ear (C).

Figure 2. Ulcers were noted on the tongue.

The clinical diagnosis was probable thrombosis of skin vessels with skin necrosis due to cocaine that was likely contaminated with levamisole. Pertinent laboratory results included the following: mild anemia and mild leukopenia; values within reference range for liver function, serum protein electrophoresis, hepatitis profile, human immunodeficiency virus 1 and 2, rapid plasma reagin, and antinuclear antibody; normal thrombotic studies for antithrombin III, protein C, protein S, factor V Leiden, prothrombin mutation G20210A, anticardiolipin IgG, IgM, and IgA; erythrocyte sedimentation rate of 
26 mm/h (reference range, 0–15 mm/h); perinuclear antineutrophil cytoplasmic antibody greater than 1:320 (reference range, <1:20) with normal proteinase 3 
and myeloperoxidase antibodies; urine positive for cocaine but blood negative for cocaine; normal chest radiograph; and normal electrocardiogram.

The patient was stable with good family support and was discharged from the emergency department to be followed in our dermatology office. The following day his skin biopsies were interpreted as neutrophilic vasculitis with extensive intravascular early and organizing thrombi involving all small- and medium-sized blood vessels consistent with levamisole-induced necrosis or septic vasculitis (Figure 3). With his history of MRSA septic arthritis and bursitis, he was hospitalized for treatment with intravenous vancomycin pending further studies. Skin biopsy for direct immunofluorescence revealed granular deposits of IgM and linear deposits of C3 at the dermoepidermal junction and in blood vessel walls. Two tissue cultures for bacteria and fungi were negative and 2 blood cultures were negative. An echocardiogram was normal and without evidence of emboli. The patient remained stable and antibiotics were discontinued. He was released from the hospital and his skin lesions healed satisfactorily with showering and mupirocin ointment.

Figure 3. Thrombotic occlusion of blood vessels was seen on histopathology (A and B)(H&E, original magnifications ×100 and ×400).

Cocaine is a white powder that is primarily derived from the leaves of the coca plant in South America. It is ingested orally; injected intravenously; snorted intranasally; chewed; eaten; used as a suppository; or dissolved in water and baking soda then heated to crystallization for smoking, which is the most addictive method and known as freebasing. When smoked, crack cocaine produces a crackling sound. Cocaine stimulates the central nervous system similar to amphetamine but may harm any body organ through vasoconstriction/vasospasm and cause skin necrosis without any additive. Perhaps less known is its ability to produce smooth muscle hyperplasia of small vessels and premature atherosclerosis.¹

Levamisole has been used to treat worms, cancer, and stimulation of the immune system but currently is used only by veterinarians because of agranulocytosis and vasculitis in humans. As of July 2009, the Drug Enforcement Agency reported that 69% of seized cocaine lots coming into the United States contained levamisole.² By January 2010, 73.2% of seized cocaine exhibits contained levamisole according to the California Poison Control System, with reports of contamination rates from across the country ranging from 40% to 90%.³ Levamisole is an inexpensive additive to cocaine and may increase the release of brain dopamine.⁴ It is difficult to detect levamisole in urine due to its short half-life of 
5.6 hours and only 2% to 5% of the parent compound being found in the urine.⁵

Skin necrosis due to cocaine-contaminated levamisole usually occurs in younger individuals who have characteristic skin lesions and a history of cocaine use. Skin lesions usually are multiple, purpuric or necrotic with irregular angulated edges and a halo of erythema. Ear involvement is common but not invariable.⁶ Descriptive adjectives include branched, netlike, retiform, and stellate, all revealing the compromised underlying dermal and subcutaneous vascular anatomy. Supportive evidence includes a decreased white blood cell count (neutropenia in up to 50%),⁵ positive antineutrophilic cytoplasmic antibodies,^5,7 and/or positive drug screen. Skin biopsy may reveal thrombosis,⁴ fibrin thrombi without vasculitis,⁸ or leukocytoclastic vasculitis,^4,5 or may suggest septic vasculitis.⁹ Direct immunofluorescence may suggest an immune complex-mediated vasculitis.⁵

The differential diagnosis for a patient with 
purpuric/necrotic skin lesions should be broad and include vasculitis (eg, inflammatory, antineutrophil cytoplasmic antibody positive, septic), hypercoagulopathy (eg, antiphospholipid syndrome, antithrombin III, prothrombin mutation G20210A, 
factor V Leiden, protein C, protein S), drugs 
(eg, heparin, warfarin, cocaine with or without levamisole, intravenous drug use, hydroxyurea, ergotamine, propylthiouracil¹⁰), calciphylaxis, 
cold-induced thrombosis, emboli (eg, atheroma, cholesterol, endocarditis, myxoma, aortic angiosarcoma, marantic), febrile ulceronecrotic Mucha-Habermann disease, infection especially if immunosuppressed (eg, disseminated Acanthamoeba/Candida/histoplasmosis/strongyloides/varicella-zoster virus, 
S aureus, streptococcus, ecthyma gangrenosum, gas gangrene, hemorrhagic smallpox, lues maligna with human immunodeficiency virus, Meleney ulcer, Rocky Mountain spotted fever, Vibrio vulnificus), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombocythemia, Waldenström hyperglobulinemic purpura, pyoderma gangrenosum, cancer (eg, paraneoplastic arterial thrombi), oxalosis, paraproteinemia (eg, multiple myeloma), and lupus with generalized coagulopathy. Less likely diagnoses might include Degos disease, factitial dermatitis, foreign bodies, multiple spider bites, paroxysmal nocturnal hemoglobinuria, sickle cell anemia, Buruli ulcer, or thromboangiitis obliterans. Branched, angulated, retiform lesions are an important finding, and some of these diagnostic possibilities are not classically retiform. However, clinical findings are not always classical, and astute physicians want to be circumspect. Had more ominous findings been present in our patient (eg, fever, hemodynamic instability, progressive skin lesions, systemic organ involvement), prompt hospitalization and additional considerations would have been necessary, such as septicemia (eg, meningococcemia, bubonic plague [Black Death], necrotizing 
fasciitis, purpura fulminans), catastrophic antiphospholipid syndrome, or disseminated intra-
vascular coagulation.

The prognosis for skin necrosis caused by 
levamisole-contaminated cocaine generally is good without long-term sequelae.⁵ Autoantibody 
serologies normalize within weeks to months after stopping levamisole.^5,8 Our patient recovered with conservative measures.

To the Editor:

Optical coherence tomography (OCT) is a 
noninvasive imaging technique that uses a 
low-power infrared laser light for cutaneous architecture visualization up to 2 mm in depth. Both malignant and nonmalignant lesions on OCT 
imaging have been correlated with histopathologic analysis.¹ We describe the diagnostic features of knuckle pads on OCT.

A 43-year-old-man presented with warts on the right thumb and bilateral feet of several months’ duration with noncontributory medical and social history. Physical examination revealed nontender, well-demarcated, flesh-colored, verrucous papules on the dorsal interphalangeal joints of the right thumb and several toes (Figure 1). Pinpoint vessels were absent on dermoscopy (Figure 2). Histopathologic analysis of a shave biopsy of the lesion on the left second toe revealed dense orthokeratosis with compact keratin, suggestive of reactive hyperkeratosis or a knuckle pad (Figure 3). In situ hybridization failed to demonstrate staining for human papillomavirus types 6, 11, and 16.

Figure 1. Verrucous papules on the left foot.		Figure 2. Corresponding dermoscopy of the left second toe revealed an absence of pinpoint vessels.

Optical coherence tomography demonstrated discrete thickening of the stratum corneum with distinctive granular and coarse textural appearance of the hyperkeratotic stratum corneum compared to normal adjacent skin. This textural difference was attributed to the alteration in collagen deposition of the knuckle pads, consistent with fibrous proliferation. Finally, OCT imaging provided further characterization of the lesion demonstrating the absence of any hair follicles and acrosyringium in areas resembling glabrous skin (Figure 4).

Figure 3. Dense orthokeratosis with compact keratin on histopathology (H&amp;E, original magnification ×40), corresponding to white hyperreflective areas on optical coherence tomography.

Figure 4. Optical coherence tomography revealed the absence of hair follicles and acrosyringium as well as the white hyperreflective areas consistent with orthokeratosis.

Knuckle pads, also known as Garrod pads, were first described by Garrod² in 1893. They are benign, asymptomatic, fibrotic thickenings of the skin. Lesions are smooth, firm, flesh colored, and located on the dorsal aspect of the hands and feet along 
the metacarpophalangeal and interphalangeal 
joints. Knuckle pads are common, can develop at any age, and are observed more frequently in men than in women.³

Primary knuckle pads can be sporadic or associated with other conditions such as palmoplantar keratoderma, acrokeratoelastoidosis costa, fibrosing disorders, or Bart-Pumphrey syndrome.⁴ Secondary knuckle pads, which are more common, occur in sites of repetitive trauma or pressure. Certain occupations (eg, mechanics) or hobbies (eg, boxing) increase the risk for developing knuckle pads.^3,4

The diagnosis of knuckle pads is usually made clinically, though several other conditions mimic knuckle pads, including scars, keloids, calluses, verruca vulgaris, fibromas, and rheumatoid nodules.^3,5 We report a description of knuckle pads that was diagnosed with OCT imaging. Further characterization of both malignant and nonmalignant lesions on OCT imaging will contribute new insights to the role of OCT in the noninvasive diagnosis of skin diseases, pending future studies.

To the Editor:

Optical coherence tomography (OCT) is a 
noninvasive imaging technique that uses a 
low-power infrared laser light for cutaneous architecture visualization up to 2 mm in depth. Both malignant and nonmalignant lesions on OCT 
imaging have been correlated with histopathologic analysis.¹ We describe the diagnostic features of knuckle pads on OCT.

A 43-year-old-man presented with warts on the right thumb and bilateral feet of several months’ duration with noncontributory medical and social history. Physical examination revealed nontender, well-demarcated, flesh-colored, verrucous papules on the dorsal interphalangeal joints of the right thumb and several toes (Figure 1). Pinpoint vessels were absent on dermoscopy (Figure 2). Histopathologic analysis of a shave biopsy of the lesion on the left second toe revealed dense orthokeratosis with compact keratin, suggestive of reactive hyperkeratosis or a knuckle pad (Figure 3). In situ hybridization failed to demonstrate staining for human papillomavirus types 6, 11, and 16.

Figure 1. Verrucous papules on the left foot.		Figure 2. Corresponding dermoscopy of the left second toe revealed an absence of pinpoint vessels.

Optical coherence tomography demonstrated discrete thickening of the stratum corneum with distinctive granular and coarse textural appearance of the hyperkeratotic stratum corneum compared to normal adjacent skin. This textural difference was attributed to the alteration in collagen deposition of the knuckle pads, consistent with fibrous proliferation. Finally, OCT imaging provided further characterization of the lesion demonstrating the absence of any hair follicles and acrosyringium in areas resembling glabrous skin (Figure 4).

Figure 3. Dense orthokeratosis with compact keratin on histopathology (H&amp;E, original magnification ×40), corresponding to white hyperreflective areas on optical coherence tomography.

Figure 4. Optical coherence tomography revealed the absence of hair follicles and acrosyringium as well as the white hyperreflective areas consistent with orthokeratosis.

Knuckle pads, also known as Garrod pads, were first described by Garrod² in 1893. They are benign, asymptomatic, fibrotic thickenings of the skin. Lesions are smooth, firm, flesh colored, and located on the dorsal aspect of the hands and feet along 
the metacarpophalangeal and interphalangeal 
joints. Knuckle pads are common, can develop at any age, and are observed more frequently in men than in women.³

Primary knuckle pads can be sporadic or associated with other conditions such as palmoplantar keratoderma, acrokeratoelastoidosis costa, fibrosing disorders, or Bart-Pumphrey syndrome.⁴ Secondary knuckle pads, which are more common, occur in sites of repetitive trauma or pressure. Certain occupations (eg, mechanics) or hobbies (eg, boxing) increase the risk for developing knuckle pads.^3,4

The diagnosis of knuckle pads is usually made clinically, though several other conditions mimic knuckle pads, including scars, keloids, calluses, verruca vulgaris, fibromas, and rheumatoid nodules.^3,5 We report a description of knuckle pads that was diagnosed with OCT imaging. Further characterization of both malignant and nonmalignant lesions on OCT imaging will contribute new insights to the role of OCT in the noninvasive diagnosis of skin diseases, pending future studies.

To the Editor:

Optical coherence tomography (OCT) is a 
noninvasive imaging technique that uses a 
low-power infrared laser light for cutaneous architecture visualization up to 2 mm in depth. Both malignant and nonmalignant lesions on OCT 
imaging have been correlated with histopathologic analysis.¹ We describe the diagnostic features of knuckle pads on OCT.

A 43-year-old-man presented with warts on the right thumb and bilateral feet of several months’ duration with noncontributory medical and social history. Physical examination revealed nontender, well-demarcated, flesh-colored, verrucous papules on the dorsal interphalangeal joints of the right thumb and several toes (Figure 1). Pinpoint vessels were absent on dermoscopy (Figure 2). Histopathologic analysis of a shave biopsy of the lesion on the left second toe revealed dense orthokeratosis with compact keratin, suggestive of reactive hyperkeratosis or a knuckle pad (Figure 3). In situ hybridization failed to demonstrate staining for human papillomavirus types 6, 11, and 16.

Figure 1. Verrucous papules on the left foot.		Figure 2. Corresponding dermoscopy of the left second toe revealed an absence of pinpoint vessels.

Optical coherence tomography demonstrated discrete thickening of the stratum corneum with distinctive granular and coarse textural appearance of the hyperkeratotic stratum corneum compared to normal adjacent skin. This textural difference was attributed to the alteration in collagen deposition of the knuckle pads, consistent with fibrous proliferation. Finally, OCT imaging provided further characterization of the lesion demonstrating the absence of any hair follicles and acrosyringium in areas resembling glabrous skin (Figure 4).

Figure 3. Dense orthokeratosis with compact keratin on histopathology (H&amp;E, original magnification ×40), corresponding to white hyperreflective areas on optical coherence tomography.

Figure 4. Optical coherence tomography revealed the absence of hair follicles and acrosyringium as well as the white hyperreflective areas consistent with orthokeratosis.

Knuckle pads, also known as Garrod pads, were first described by Garrod² in 1893. They are benign, asymptomatic, fibrotic thickenings of the skin. Lesions are smooth, firm, flesh colored, and located on the dorsal aspect of the hands and feet along 
the metacarpophalangeal and interphalangeal 
joints. Knuckle pads are common, can develop at any age, and are observed more frequently in men than in women.³

Primary knuckle pads can be sporadic or associated with other conditions such as palmoplantar keratoderma, acrokeratoelastoidosis costa, fibrosing disorders, or Bart-Pumphrey syndrome.⁴ Secondary knuckle pads, which are more common, occur in sites of repetitive trauma or pressure. Certain occupations (eg, mechanics) or hobbies (eg, boxing) increase the risk for developing knuckle pads.^3,4

The diagnosis of knuckle pads is usually made clinically, though several other conditions mimic knuckle pads, including scars, keloids, calluses, verruca vulgaris, fibromas, and rheumatoid nodules.^3,5 We report a description of knuckle pads that was diagnosed with OCT imaging. Further characterization of both malignant and nonmalignant lesions on OCT imaging will contribute new insights to the role of OCT in the noninvasive diagnosis of skin diseases, pending future studies.

To the Editor:

A 62-year-old woman with an extensive history of cutaneous and oral lichen planus (OLP) presented with gradual worsening of oral pain refractory to previously successful treatment regimens. The pains were described as sharp sensations originating in the right superior oral cavity, occurring almost constantly over the course of 2 months. On examination, the oral mucosa on the right side showed lacy, white, hyperkeratotic buccal lesions, as well as superficial erythematous erosion on the right upper alveolar ridge mucosa (Figure 1). On the left side, lacy, white, reticular patches were noted along the buccal mucosa. Gingival desquamation with superficial erosions were observed bilaterally, extending to the upper alveolar ridge in some locations. The skin examination revealed resolving, nonirritated, violaceous, flat-topped papules with a white-gray hue on the upper back and vulva.

Figure 1. Erosive oral lichen planus of the right maxillary alveolar ridge.

The rest of the physical examination was benign, including a lack of appreciable lymphadenopathy, a cranial nerve examination without focal deficit, and the presence of fluent unaffected speech. On review of systems, the patient denied fevers, chills, weight loss, or night sweats. She had no history of skin cancer or oropharyngeal cancer. Family history revealed that her father had nonmelanoma skin cancer of the head and neck. She denied heavy alcohol use as well as history of smoking or other oral tobacco products. Laboratory tests revealed a complete blood cell count and comprehensive metabolic panel that was within reference range. Due to the refractory nature of the pain, which was out of character for OLP, the patient was referred to an oral maxillofacial surgeon who extracted right maxillary teeth adjacent to the erosion to obtain an adequate specimen for surgical biopsy of the lesion itself. Histopathology confirmed the diagnosis of chronic erosive OLP with malignant transformation to localized squamous cell carcinoma (SCC) of the right maxilla.

While awaiting treatment, she began to develop unremitting headaches and painful shooting sensations beginning in the right superior oral mucosa, radiating to the ipsilateral naris, nasolabial folds, malar cheek, and temple region. This clinical picture was consistent with neuralgia occurring along the maxillary nerve. A subsequent computed tomography scan revealed local bony destruction of the primary tumor and likely perineural involvement (Figure 2), without notable nodal involvement or metastasis (stage III: T4aN0M0). An otolaryngologist performed a wide alveolar and maxillary excision with lymph node dissection. Surgical margins were deemed as negative and there was no evidence of nodal disease. She was later seen by the oncology and radiation oncology teams and received several courses of chemoradiotherapy.

Figure 2. Coronal (A) and axial (B) computed tomography demonstrated right maxillary bony destruction.

Seven months later, a new indurated ulcer was noted on the left lateral tongue. Biopsy revealed a new primary oral SCC (OSCC), which also was excised by an otolaryngologist. Recent computed tomography did not detect any recurrence or potential metastases, but the patient subsequently was lost to follow-up.

Lichen planus is an idiopathic inflammatory disease most commonly affecting the cutaneous skin as well as the oral mucosa, genital mucosa, nails, and scalp. Oral lichen planus is a relatively common manifestation, found in approximately 1% to 2% of individuals older than 15 years.¹ Epidemiologic studies revealed that OLP is uncommon in children,^2,3 it affects women more frequently than men (approximately 3:1 ratio),³ and its incidence peaks between 30 and 60 years of age.⁴ The literature on malignant transformation of OLP is varied and controversial, with some early investigations such as Krutchkoff et al⁵ concluding that the reported cases often fall short of supporting OLP as a premalignant source of OSCC due to insufficient evidence in claimed case reports supporting the diagnosis of OLP histopathologically, the occurrence of OSCC in sites where OLP lesions did not previously exist, and uncertainty regarding confounding factors such as carcinogen exposure.⁵ In contrast, a longitudinal cohort study reported malignant transformation in 2.4% of 
OLP cases (N=327), with a standardized incidence ratio of 17.7 (95% confidence interval, 8.8-35.3) when compared to a control group.⁶ Current literature has predominantly sided with the notion that OLP, especially the erosive variant, carries the risk for malignant potential⁶ as well as the World Health Organization’s classification of the disorder as precancerous.³

The pathophysiology of OLP and its potential for malignant transformation are unknown. It is believed that cell-mediated immunity, specifically CD8⁺ lymphocytes targeting stratum basale keratinocytes for apoptosis via the caspase cascade, plays a major role in the development of OLP, beginning with Langerhans cell recognition of an unknown basal cell antigen.³ Moreover, it is postulated that antigen expression is induced by certain drugs, infections, and contact allergens such as dental amalgams, explaining their known associations with OLP initiation and exacerbation. The etiology behind OLP developing into OSCC also is poorly understood and many different hypotheses have been suggested. Modified expression of p53, a 53-kd protein, in OLP patients has been demonstrated.⁶ Some investigators propose that a lack of the expected keratinocyte apoptotic response to the cell-mediated attack may be etiologic in cancerous transformation.³ Given their utility in treatment of OLP, there also has been apprehension over the potential for immunosuppressant medications leading to decreased expression of antitumor regulators and development of malignant cells, though it has not been substantiated by current literature.⁶ Finally, some cases of OSCC are believed to have been linked to N-nitrosobenzylmethylamine, a known carcinogen produced by colonized Candida albicans, which also may play a role in OLP treated with immunosuppressants.⁷

Clinically, OLP lesions are known to be more chronic in nature than cutaneous lichen planus.⁷ There are 6 classifications of OLP: reticular (lacy white with Wickham striae), plaquelike, papular, atrophic, bullous, and erosive. The latter 3 are known to be the more symptomatic manifestations.^3,7 Of note, the atrophic and erosive forms are believed to account for the vast majority of cases of malignant transformation of OLP to OSCC. Approximately 90% of patients have involvement of multiple oral sites, with the most common affected areas being the buccal mucosa (90%), gingival margin (56%), and dorsal tongue (34%).⁷ Symptoms include increased sensitivity to foods, intense local pain, and coarse-feeling mucosa. The nature of the disease favors an active-quiescent-active course, with flares occurring after direct irritation (ie, dental procedures, Köbner phenomenon), emotional stress, medication use, and systemic illness.⁷ The differential diagnosis of OLP includes bite trauma, candidiasis, pemphigus, leukoplakia, lichenoid drug reaction, pemphigoid, and graft-versus-host disease.⁴ Red flags of malignant transformation include induration, worsening ulceration in the setting of previously effective therapy, and presence of constitutional symptoms.

Regarding the behavior of OSCC after malignant transformation, the literature seems to suggest a tendency for well-differentiated noninvasive tumors that most often occur on the buccal mucosa (43%), tongue (33%), gingiva (19%), and palate (4.8%).⁸ Interestingly, one study described that only 1 (4.8%) of 21 patients with OLP and OSCC was deemed as having stage II or higher disease at time of diagnosis. Likewise, 90% of the biopsied samples revealed well-differentiated carcinomas.⁸ These findings clearly contrast with our case in which the patient experienced rapid conversion of localized OSCC to more invasive disease. Also of consequence in this study was the finding that a relatively high proportion of patients (29% [6/21]) developed at least one other primary OSCC lesion over the course of follow-up.⁸ This finding is consistent with our patient.

Last, management of OLP lesions is most commonly accomplished with topical steroids such as fluocinolone acetonide or triamcinolone acetonide.³ Treatment of gingival disease may be enhanced with the use of form-fitting trays.² For refractory erosive disease, tacrolimus ointment has been demonstrated as a useful backup therapy but may actually be associated with the development of OSCC through alteration of MAPK and p53.³ Some investigators suggest regular 4-month 
follow-up of OLP patients to detect if acute worsening and or refractoriness to treatment have signified early dysplastic change. Various scoring systems also have been suggested for following up on the severity of OLP lesions.³

The management of OSCC usually is accomplished via surgery, radiation, or both. The decision is dependent on tumor stage and the patient’s individual limitations. It is highly recommended that patients with OSCC arising from OLP be closely followed after diagnosis of cancer, with some sources suggesting follow-up every 2 months for the first 6 to 9 months after diagnosis due to the relatively high rate of discovery of nodal metastases and new primary lesions in that critical time span.⁸ Thereafter, an examination every 4 months is suggested as sufficient for detecting future complications.

To the Editor:

A 62-year-old woman with an extensive history of cutaneous and oral lichen planus (OLP) presented with gradual worsening of oral pain refractory to previously successful treatment regimens. The pains were described as sharp sensations originating in the right superior oral cavity, occurring almost constantly over the course of 2 months. On examination, the oral mucosa on the right side showed lacy, white, hyperkeratotic buccal lesions, as well as superficial erythematous erosion on the right upper alveolar ridge mucosa (Figure 1). On the left side, lacy, white, reticular patches were noted along the buccal mucosa. Gingival desquamation with superficial erosions were observed bilaterally, extending to the upper alveolar ridge in some locations. The skin examination revealed resolving, nonirritated, violaceous, flat-topped papules with a white-gray hue on the upper back and vulva.

Figure 1. Erosive oral lichen planus of the right maxillary alveolar ridge.

The rest of the physical examination was benign, including a lack of appreciable lymphadenopathy, a cranial nerve examination without focal deficit, and the presence of fluent unaffected speech. On review of systems, the patient denied fevers, chills, weight loss, or night sweats. She had no history of skin cancer or oropharyngeal cancer. Family history revealed that her father had nonmelanoma skin cancer of the head and neck. She denied heavy alcohol use as well as history of smoking or other oral tobacco products. Laboratory tests revealed a complete blood cell count and comprehensive metabolic panel that was within reference range. Due to the refractory nature of the pain, which was out of character for OLP, the patient was referred to an oral maxillofacial surgeon who extracted right maxillary teeth adjacent to the erosion to obtain an adequate specimen for surgical biopsy of the lesion itself. Histopathology confirmed the diagnosis of chronic erosive OLP with malignant transformation to localized squamous cell carcinoma (SCC) of the right maxilla.

While awaiting treatment, she began to develop unremitting headaches and painful shooting sensations beginning in the right superior oral mucosa, radiating to the ipsilateral naris, nasolabial folds, malar cheek, and temple region. This clinical picture was consistent with neuralgia occurring along the maxillary nerve. A subsequent computed tomography scan revealed local bony destruction of the primary tumor and likely perineural involvement (Figure 2), without notable nodal involvement or metastasis (stage III: T4aN0M0). An otolaryngologist performed a wide alveolar and maxillary excision with lymph node dissection. Surgical margins were deemed as negative and there was no evidence of nodal disease. She was later seen by the oncology and radiation oncology teams and received several courses of chemoradiotherapy.

Figure 2. Coronal (A) and axial (B) computed tomography demonstrated right maxillary bony destruction.

Seven months later, a new indurated ulcer was noted on the left lateral tongue. Biopsy revealed a new primary oral SCC (OSCC), which also was excised by an otolaryngologist. Recent computed tomography did not detect any recurrence or potential metastases, but the patient subsequently was lost to follow-up.

Lichen planus is an idiopathic inflammatory disease most commonly affecting the cutaneous skin as well as the oral mucosa, genital mucosa, nails, and scalp. Oral lichen planus is a relatively common manifestation, found in approximately 1% to 2% of individuals older than 15 years.¹ Epidemiologic studies revealed that OLP is uncommon in children,^2,3 it affects women more frequently than men (approximately 3:1 ratio),³ and its incidence peaks between 30 and 60 years of age.⁴ The literature on malignant transformation of OLP is varied and controversial, with some early investigations such as Krutchkoff et al⁵ concluding that the reported cases often fall short of supporting OLP as a premalignant source of OSCC due to insufficient evidence in claimed case reports supporting the diagnosis of OLP histopathologically, the occurrence of OSCC in sites where OLP lesions did not previously exist, and uncertainty regarding confounding factors such as carcinogen exposure.⁵ In contrast, a longitudinal cohort study reported malignant transformation in 2.4% of 
OLP cases (N=327), with a standardized incidence ratio of 17.7 (95% confidence interval, 8.8-35.3) when compared to a control group.⁶ Current literature has predominantly sided with the notion that OLP, especially the erosive variant, carries the risk for malignant potential⁶ as well as the World Health Organization’s classification of the disorder as precancerous.³

The pathophysiology of OLP and its potential for malignant transformation are unknown. It is believed that cell-mediated immunity, specifically CD8⁺ lymphocytes targeting stratum basale keratinocytes for apoptosis via the caspase cascade, plays a major role in the development of OLP, beginning with Langerhans cell recognition of an unknown basal cell antigen.³ Moreover, it is postulated that antigen expression is induced by certain drugs, infections, and contact allergens such as dental amalgams, explaining their known associations with OLP initiation and exacerbation. The etiology behind OLP developing into OSCC also is poorly understood and many different hypotheses have been suggested. Modified expression of p53, a 53-kd protein, in OLP patients has been demonstrated.⁶ Some investigators propose that a lack of the expected keratinocyte apoptotic response to the cell-mediated attack may be etiologic in cancerous transformation.³ Given their utility in treatment of OLP, there also has been apprehension over the potential for immunosuppressant medications leading to decreased expression of antitumor regulators and development of malignant cells, though it has not been substantiated by current literature.⁶ Finally, some cases of OSCC are believed to have been linked to N-nitrosobenzylmethylamine, a known carcinogen produced by colonized Candida albicans, which also may play a role in OLP treated with immunosuppressants.⁷

Clinically, OLP lesions are known to be more chronic in nature than cutaneous lichen planus.⁷ There are 6 classifications of OLP: reticular (lacy white with Wickham striae), plaquelike, papular, atrophic, bullous, and erosive. The latter 3 are known to be the more symptomatic manifestations.^3,7 Of note, the atrophic and erosive forms are believed to account for the vast majority of cases of malignant transformation of OLP to OSCC. Approximately 90% of patients have involvement of multiple oral sites, with the most common affected areas being the buccal mucosa (90%), gingival margin (56%), and dorsal tongue (34%).⁷ Symptoms include increased sensitivity to foods, intense local pain, and coarse-feeling mucosa. The nature of the disease favors an active-quiescent-active course, with flares occurring after direct irritation (ie, dental procedures, Köbner phenomenon), emotional stress, medication use, and systemic illness.⁷ The differential diagnosis of OLP includes bite trauma, candidiasis, pemphigus, leukoplakia, lichenoid drug reaction, pemphigoid, and graft-versus-host disease.⁴ Red flags of malignant transformation include induration, worsening ulceration in the setting of previously effective therapy, and presence of constitutional symptoms.

Regarding the behavior of OSCC after malignant transformation, the literature seems to suggest a tendency for well-differentiated noninvasive tumors that most often occur on the buccal mucosa (43%), tongue (33%), gingiva (19%), and palate (4.8%).⁸ Interestingly, one study described that only 1 (4.8%) of 21 patients with OLP and OSCC was deemed as having stage II or higher disease at time of diagnosis. Likewise, 90% of the biopsied samples revealed well-differentiated carcinomas.⁸ These findings clearly contrast with our case in which the patient experienced rapid conversion of localized OSCC to more invasive disease. Also of consequence in this study was the finding that a relatively high proportion of patients (29% [6/21]) developed at least one other primary OSCC lesion over the course of follow-up.⁸ This finding is consistent with our patient.

Last, management of OLP lesions is most commonly accomplished with topical steroids such as fluocinolone acetonide or triamcinolone acetonide.³ Treatment of gingival disease may be enhanced with the use of form-fitting trays.² For refractory erosive disease, tacrolimus ointment has been demonstrated as a useful backup therapy but may actually be associated with the development of OSCC through alteration of MAPK and p53.³ Some investigators suggest regular 4-month 
follow-up of OLP patients to detect if acute worsening and or refractoriness to treatment have signified early dysplastic change. Various scoring systems also have been suggested for following up on the severity of OLP lesions.³

The management of OSCC usually is accomplished via surgery, radiation, or both. The decision is dependent on tumor stage and the patient’s individual limitations. It is highly recommended that patients with OSCC arising from OLP be closely followed after diagnosis of cancer, with some sources suggesting follow-up every 2 months for the first 6 to 9 months after diagnosis due to the relatively high rate of discovery of nodal metastases and new primary lesions in that critical time span.⁸ Thereafter, an examination every 4 months is suggested as sufficient for detecting future complications.

To the Editor:

A 62-year-old woman with an extensive history of cutaneous and oral lichen planus (OLP) presented with gradual worsening of oral pain refractory to previously successful treatment regimens. The pains were described as sharp sensations originating in the right superior oral cavity, occurring almost constantly over the course of 2 months. On examination, the oral mucosa on the right side showed lacy, white, hyperkeratotic buccal lesions, as well as superficial erythematous erosion on the right upper alveolar ridge mucosa (Figure 1). On the left side, lacy, white, reticular patches were noted along the buccal mucosa. Gingival desquamation with superficial erosions were observed bilaterally, extending to the upper alveolar ridge in some locations. The skin examination revealed resolving, nonirritated, violaceous, flat-topped papules with a white-gray hue on the upper back and vulva.

Figure 1. Erosive oral lichen planus of the right maxillary alveolar ridge.

The rest of the physical examination was benign, including a lack of appreciable lymphadenopathy, a cranial nerve examination without focal deficit, and the presence of fluent unaffected speech. On review of systems, the patient denied fevers, chills, weight loss, or night sweats. She had no history of skin cancer or oropharyngeal cancer. Family history revealed that her father had nonmelanoma skin cancer of the head and neck. She denied heavy alcohol use as well as history of smoking or other oral tobacco products. Laboratory tests revealed a complete blood cell count and comprehensive metabolic panel that was within reference range. Due to the refractory nature of the pain, which was out of character for OLP, the patient was referred to an oral maxillofacial surgeon who extracted right maxillary teeth adjacent to the erosion to obtain an adequate specimen for surgical biopsy of the lesion itself. Histopathology confirmed the diagnosis of chronic erosive OLP with malignant transformation to localized squamous cell carcinoma (SCC) of the right maxilla.

While awaiting treatment, she began to develop unremitting headaches and painful shooting sensations beginning in the right superior oral mucosa, radiating to the ipsilateral naris, nasolabial folds, malar cheek, and temple region. This clinical picture was consistent with neuralgia occurring along the maxillary nerve. A subsequent computed tomography scan revealed local bony destruction of the primary tumor and likely perineural involvement (Figure 2), without notable nodal involvement or metastasis (stage III: T4aN0M0). An otolaryngologist performed a wide alveolar and maxillary excision with lymph node dissection. Surgical margins were deemed as negative and there was no evidence of nodal disease. She was later seen by the oncology and radiation oncology teams and received several courses of chemoradiotherapy.

Figure 2. Coronal (A) and axial (B) computed tomography demonstrated right maxillary bony destruction.

Seven months later, a new indurated ulcer was noted on the left lateral tongue. Biopsy revealed a new primary oral SCC (OSCC), which also was excised by an otolaryngologist. Recent computed tomography did not detect any recurrence or potential metastases, but the patient subsequently was lost to follow-up.

Lichen planus is an idiopathic inflammatory disease most commonly affecting the cutaneous skin as well as the oral mucosa, genital mucosa, nails, and scalp. Oral lichen planus is a relatively common manifestation, found in approximately 1% to 2% of individuals older than 15 years.¹ Epidemiologic studies revealed that OLP is uncommon in children,^2,3 it affects women more frequently than men (approximately 3:1 ratio),³ and its incidence peaks between 30 and 60 years of age.⁴ The literature on malignant transformation of OLP is varied and controversial, with some early investigations such as Krutchkoff et al⁵ concluding that the reported cases often fall short of supporting OLP as a premalignant source of OSCC due to insufficient evidence in claimed case reports supporting the diagnosis of OLP histopathologically, the occurrence of OSCC in sites where OLP lesions did not previously exist, and uncertainty regarding confounding factors such as carcinogen exposure.⁵ In contrast, a longitudinal cohort study reported malignant transformation in 2.4% of 
OLP cases (N=327), with a standardized incidence ratio of 17.7 (95% confidence interval, 8.8-35.3) when compared to a control group.⁶ Current literature has predominantly sided with the notion that OLP, especially the erosive variant, carries the risk for malignant potential⁶ as well as the World Health Organization’s classification of the disorder as precancerous.³

The pathophysiology of OLP and its potential for malignant transformation are unknown. It is believed that cell-mediated immunity, specifically CD8⁺ lymphocytes targeting stratum basale keratinocytes for apoptosis via the caspase cascade, plays a major role in the development of OLP, beginning with Langerhans cell recognition of an unknown basal cell antigen.³ Moreover, it is postulated that antigen expression is induced by certain drugs, infections, and contact allergens such as dental amalgams, explaining their known associations with OLP initiation and exacerbation. The etiology behind OLP developing into OSCC also is poorly understood and many different hypotheses have been suggested. Modified expression of p53, a 53-kd protein, in OLP patients has been demonstrated.⁶ Some investigators propose that a lack of the expected keratinocyte apoptotic response to the cell-mediated attack may be etiologic in cancerous transformation.³ Given their utility in treatment of OLP, there also has been apprehension over the potential for immunosuppressant medications leading to decreased expression of antitumor regulators and development of malignant cells, though it has not been substantiated by current literature.⁶ Finally, some cases of OSCC are believed to have been linked to N-nitrosobenzylmethylamine, a known carcinogen produced by colonized Candida albicans, which also may play a role in OLP treated with immunosuppressants.⁷

Clinically, OLP lesions are known to be more chronic in nature than cutaneous lichen planus.⁷ There are 6 classifications of OLP: reticular (lacy white with Wickham striae), plaquelike, papular, atrophic, bullous, and erosive. The latter 3 are known to be the more symptomatic manifestations.^3,7 Of note, the atrophic and erosive forms are believed to account for the vast majority of cases of malignant transformation of OLP to OSCC. Approximately 90% of patients have involvement of multiple oral sites, with the most common affected areas being the buccal mucosa (90%), gingival margin (56%), and dorsal tongue (34%).⁷ Symptoms include increased sensitivity to foods, intense local pain, and coarse-feeling mucosa. The nature of the disease favors an active-quiescent-active course, with flares occurring after direct irritation (ie, dental procedures, Köbner phenomenon), emotional stress, medication use, and systemic illness.⁷ The differential diagnosis of OLP includes bite trauma, candidiasis, pemphigus, leukoplakia, lichenoid drug reaction, pemphigoid, and graft-versus-host disease.⁴ Red flags of malignant transformation include induration, worsening ulceration in the setting of previously effective therapy, and presence of constitutional symptoms.

Regarding the behavior of OSCC after malignant transformation, the literature seems to suggest a tendency for well-differentiated noninvasive tumors that most often occur on the buccal mucosa (43%), tongue (33%), gingiva (19%), and palate (4.8%).⁸ Interestingly, one study described that only 1 (4.8%) of 21 patients with OLP and OSCC was deemed as having stage II or higher disease at time of diagnosis. Likewise, 90% of the biopsied samples revealed well-differentiated carcinomas.⁸ These findings clearly contrast with our case in which the patient experienced rapid conversion of localized OSCC to more invasive disease. Also of consequence in this study was the finding that a relatively high proportion of patients (29% [6/21]) developed at least one other primary OSCC lesion over the course of follow-up.⁸ This finding is consistent with our patient.

Last, management of OLP lesions is most commonly accomplished with topical steroids such as fluocinolone acetonide or triamcinolone acetonide.³ Treatment of gingival disease may be enhanced with the use of form-fitting trays.² For refractory erosive disease, tacrolimus ointment has been demonstrated as a useful backup therapy but may actually be associated with the development of OSCC through alteration of MAPK and p53.³ Some investigators suggest regular 4-month 
follow-up of OLP patients to detect if acute worsening and or refractoriness to treatment have signified early dysplastic change. Various scoring systems also have been suggested for following up on the severity of OLP lesions.³

The management of OSCC usually is accomplished via surgery, radiation, or both. The decision is dependent on tumor stage and the patient’s individual limitations. It is highly recommended that patients with OSCC arising from OLP be closely followed after diagnosis of cancer, with some sources suggesting follow-up every 2 months for the first 6 to 9 months after diagnosis due to the relatively high rate of discovery of nodal metastases and new primary lesions in that critical time span.⁸ Thereafter, an examination every 4 months is suggested as sufficient for detecting future complications.

To the Editor:

A 51-year-old woman presented to her dermatologist with recurrent and progressive upper lip swelling of 2 years’ duration. Her condition was previously evaluated by several other physicians without a diagnosis or resolution of the symptoms. The swelling began on the right side of the upper lip and right cheek; however, over the course of 2 years, the swelling had progressed to involve the entire upper lip with complete sparing of the lower lip. She denied pain but reported numbness of the upper lip. The patient visited her dentist who ruled out periodontal infection as the cause of the swelling. Diphenhydramine provided no relief; however, the cheek swelling resolved after a course of antibiotics prescribed by an ear, nose, and throat physician.

She consulted her primary care physician and was subsequently referred to a neurologist and allergist who were unable to provide a definitive diagnosis or complete relief of the symptoms. She denied any history of hypersensitivity reactions, odontogenic infections, gastrointestinal concerns, or any other signs or symptoms of systemic granulomatous disease.

Figure 1. Upper lip swelling without ulceration, fissuring, or scaling. The lower lip was completely spared.

On physical examination, the upper lip was swollen symmetrically without evidence of ulceration, fissuring, or scaling (Figure 1). Palpation of the upper lip was notable for firm, nontender, nonpitting edema without nodularity. The oral mucosa did not appear swollen or erythematous. Examination did not reveal ulceration or a cobblestone appearance.

A full-thickness skin biopsy of the upper lip was performed. Histopathology revealed perivascular nonnecrotizing granulomas adjacent to ectatic vascular channels with associated lymphoplasmacytic infiltrate (Figure 2). Periodic acid–Schiff stain was negative for fungal hyphae, tissue Gram stain was negative for bacteria, Fite and acid-fast bacillus stains were both negative for acid-fast organisms, and polariscopy was negative for polarizable foreign material. In this clinical context, the morphologic findings were consistent with the diagnosis of granulomatous cheilitis (GC).

Figure 2. Upper lip biopsy showed dermal edema, vascular ectasia, perivascular nonnecrotizing granulomas, and perivascular lymphocyte predominant inflammatory infiltrate (A)(H&E, original magnification ×100). Higher magnification of granulomas with perivascular lymphoplasmacytic infiltrate (B)(H&E, original magnification ×200).

Granulomatous cheilitis is a rare disorder of the lips and orofacial mucosa that was first described by Meischer¹ in 1945 as persistent or recurrent orofacial swelling secondary to lymphatic obstruction by granulomatous proliferation. It often has been described as a monosymptomatic form of Melkersson-Rosenthal syndrome (MRS). In its entirety, MRS constitutes a triad of GC, facial nerve palsy, and lingua plicata (also known as fissured tongue).^2,3 Although many authors agree that GC is associated with MRS, some believe that GC is a distinct entity because the majority of patients who present with GC subsequently do not develop MRS.⁴ Despite its relationship to MRS, the true incidence of GC largely is unknown. The onset of disease usually occurs in early adulthood but can present in middle-aged or older individuals.

The typical course of GC is relapsing and remitting, nontender and nonpitting swelling of the lips that eventually becomes permanent, leading to possible facial distortion and disability. Involvement of the upper lip is the most common, followed by (in order of decreasing frequency) the lower lip and cheeks.⁵ The swelling may be unilateral or bilateral and generally is not associated with ulceration, fissuring, or scaling; however, these complications have been reported in the terminal stages of the disease in which the macrocheilia has become permanent.

Despite the controversy over the etiology, pathophysiology, and classification of GC, it largely is accepted that when a patient presents clinically with a history of recurrent or persistent lip swelling, a 
full-thickness skin biopsy of the involved oral mucosa should be taken. Conditions that are considered in the differential diagnosis of orofacial granulomatosis are systemic granulomatous diseases that are known to have oral manifestations including Crohn disease, sarcoidosis, and mycobacterial infections. Given the many causes of orofacial and labial swelling, GC is a diagnosis of exclusion based on a thorough history and physical examination as well as appropriate diagnostic studies, with the cornerstone of the diagnosis resting on the histologic appearance of the lesion. Histologically, the diagnosis lies in the demonstration of granuloma formation, consisting of collections of epithelioid histiocytes and Langerhans giant cells. Once granuloma formation is documented, special stains are used to rule out other granulomatous diseases.

Intralesional steroids have been reported to provide the greatest improvement; however, in the majority of patients, multiple treatments are required.^6,7 Allen et al⁸ suggested that the efficacy of intralesional therapy increases when preceded by local anesthesia of the lip, thus allowing larger doses of triamcinolone to be tolerated by the patient. Systemic corticosteroids also have been used with moderate success, but the side effects of long-term systemic corticosteroid therapy make this treatment option less appealing.⁹ Other agents with known anti-inflammatory properties also have been used that may offer better side-effect profiles when used for long-term suppressive therapy, including 
clofazimine, dapsone, sulfapyridine, danazol, hydroxychloroquine, and antibiotics such as doxycycline and metronidazole.¹⁰

In severe or recalcitrant cases, surgical intervention by way of a reduction cheiloplasty is considered by some to be an appropriate next step in therapy but is rarely needed. Postoperative intralesional steroid injections are necessary due to reported cases of worsening disease when injections are discontinued after cheiloplasty.^11,12

Our patient was treated with 5 mg of intralesional triamcinolone acetonide with 10 separate injections of 0.5 cc each along the affected portions of the upper lip. She also was given doxycycline 100 mg once daily for 30 days. The patient reported complete resolution of the upper lip swelling 7 days after the initiation of therapy. At 1-month follow-up, she reported that the swelling had completely resolved. However, 1 day prior to the scheduled visit, shortly after finishing the course of doxycycline, she noted recurrent swelling. Due to the concomitant initial administration of both the steroid injections and doxycycline, it was unclear which treatment had provided relief. To avoid, or at least delay, the need for chronic intralesional steroid injections, another course of 40 mg doxycycline daily was prescribed. After 2 weeks, the patient reported that the swelling had markedly improved. The patient has 
maintained remission of the symptoms for approximately 6 months on daily suppressive therapy with 40 mg of doxycycline.

The recurrence of lip swelling after therapy, as in our patient, is typical of GC, and most cases require multiple follow-up visits and frequent alterations in therapy, which is often frustrating for both the patient and physician. However, awareness of this disease entity, its natural course, and the therapeutic options will allow physicians to more appropriately counsel and educate patients of this uncommon 
disease process.

To the Editor:

A 51-year-old woman presented to her dermatologist with recurrent and progressive upper lip swelling of 2 years’ duration. Her condition was previously evaluated by several other physicians without a diagnosis or resolution of the symptoms. The swelling began on the right side of the upper lip and right cheek; however, over the course of 2 years, the swelling had progressed to involve the entire upper lip with complete sparing of the lower lip. She denied pain but reported numbness of the upper lip. The patient visited her dentist who ruled out periodontal infection as the cause of the swelling. Diphenhydramine provided no relief; however, the cheek swelling resolved after a course of antibiotics prescribed by an ear, nose, and throat physician.

She consulted her primary care physician and was subsequently referred to a neurologist and allergist who were unable to provide a definitive diagnosis or complete relief of the symptoms. She denied any history of hypersensitivity reactions, odontogenic infections, gastrointestinal concerns, or any other signs or symptoms of systemic granulomatous disease.

Figure 1. Upper lip swelling without ulceration, fissuring, or scaling. The lower lip was completely spared.

On physical examination, the upper lip was swollen symmetrically without evidence of ulceration, fissuring, or scaling (Figure 1). Palpation of the upper lip was notable for firm, nontender, nonpitting edema without nodularity. The oral mucosa did not appear swollen or erythematous. Examination did not reveal ulceration or a cobblestone appearance.

A full-thickness skin biopsy of the upper lip was performed. Histopathology revealed perivascular nonnecrotizing granulomas adjacent to ectatic vascular channels with associated lymphoplasmacytic infiltrate (Figure 2). Periodic acid–Schiff stain was negative for fungal hyphae, tissue Gram stain was negative for bacteria, Fite and acid-fast bacillus stains were both negative for acid-fast organisms, and polariscopy was negative for polarizable foreign material. In this clinical context, the morphologic findings were consistent with the diagnosis of granulomatous cheilitis (GC).

Figure 2. Upper lip biopsy showed dermal edema, vascular ectasia, perivascular nonnecrotizing granulomas, and perivascular lymphocyte predominant inflammatory infiltrate (A)(H&E, original magnification ×100). Higher magnification of granulomas with perivascular lymphoplasmacytic infiltrate (B)(H&E, original magnification ×200).

Granulomatous cheilitis is a rare disorder of the lips and orofacial mucosa that was first described by Meischer¹ in 1945 as persistent or recurrent orofacial swelling secondary to lymphatic obstruction by granulomatous proliferation. It often has been described as a monosymptomatic form of Melkersson-Rosenthal syndrome (MRS). In its entirety, MRS constitutes a triad of GC, facial nerve palsy, and lingua plicata (also known as fissured tongue).^2,3 Although many authors agree that GC is associated with MRS, some believe that GC is a distinct entity because the majority of patients who present with GC subsequently do not develop MRS.⁴ Despite its relationship to MRS, the true incidence of GC largely is unknown. The onset of disease usually occurs in early adulthood but can present in middle-aged or older individuals.

The typical course of GC is relapsing and remitting, nontender and nonpitting swelling of the lips that eventually becomes permanent, leading to possible facial distortion and disability. Involvement of the upper lip is the most common, followed by (in order of decreasing frequency) the lower lip and cheeks.⁵ The swelling may be unilateral or bilateral and generally is not associated with ulceration, fissuring, or scaling; however, these complications have been reported in the terminal stages of the disease in which the macrocheilia has become permanent.

Despite the controversy over the etiology, pathophysiology, and classification of GC, it largely is accepted that when a patient presents clinically with a history of recurrent or persistent lip swelling, a 
full-thickness skin biopsy of the involved oral mucosa should be taken. Conditions that are considered in the differential diagnosis of orofacial granulomatosis are systemic granulomatous diseases that are known to have oral manifestations including Crohn disease, sarcoidosis, and mycobacterial infections. Given the many causes of orofacial and labial swelling, GC is a diagnosis of exclusion based on a thorough history and physical examination as well as appropriate diagnostic studies, with the cornerstone of the diagnosis resting on the histologic appearance of the lesion. Histologically, the diagnosis lies in the demonstration of granuloma formation, consisting of collections of epithelioid histiocytes and Langerhans giant cells. Once granuloma formation is documented, special stains are used to rule out other granulomatous diseases.

Intralesional steroids have been reported to provide the greatest improvement; however, in the majority of patients, multiple treatments are required.^6,7 Allen et al⁸ suggested that the efficacy of intralesional therapy increases when preceded by local anesthesia of the lip, thus allowing larger doses of triamcinolone to be tolerated by the patient. Systemic corticosteroids also have been used with moderate success, but the side effects of long-term systemic corticosteroid therapy make this treatment option less appealing.⁹ Other agents with known anti-inflammatory properties also have been used that may offer better side-effect profiles when used for long-term suppressive therapy, including 
clofazimine, dapsone, sulfapyridine, danazol, hydroxychloroquine, and antibiotics such as doxycycline and metronidazole.¹⁰

In severe or recalcitrant cases, surgical intervention by way of a reduction cheiloplasty is considered by some to be an appropriate next step in therapy but is rarely needed. Postoperative intralesional steroid injections are necessary due to reported cases of worsening disease when injections are discontinued after cheiloplasty.^11,12

Our patient was treated with 5 mg of intralesional triamcinolone acetonide with 10 separate injections of 0.5 cc each along the affected portions of the upper lip. She also was given doxycycline 100 mg once daily for 30 days. The patient reported complete resolution of the upper lip swelling 7 days after the initiation of therapy. At 1-month follow-up, she reported that the swelling had completely resolved. However, 1 day prior to the scheduled visit, shortly after finishing the course of doxycycline, she noted recurrent swelling. Due to the concomitant initial administration of both the steroid injections and doxycycline, it was unclear which treatment had provided relief. To avoid, or at least delay, the need for chronic intralesional steroid injections, another course of 40 mg doxycycline daily was prescribed. After 2 weeks, the patient reported that the swelling had markedly improved. The patient has 
maintained remission of the symptoms for approximately 6 months on daily suppressive therapy with 40 mg of doxycycline.

The recurrence of lip swelling after therapy, as in our patient, is typical of GC, and most cases require multiple follow-up visits and frequent alterations in therapy, which is often frustrating for both the patient and physician. However, awareness of this disease entity, its natural course, and the therapeutic options will allow physicians to more appropriately counsel and educate patients of this uncommon 
disease process.

To the Editor:

A 51-year-old woman presented to her dermatologist with recurrent and progressive upper lip swelling of 2 years’ duration. Her condition was previously evaluated by several other physicians without a diagnosis or resolution of the symptoms. The swelling began on the right side of the upper lip and right cheek; however, over the course of 2 years, the swelling had progressed to involve the entire upper lip with complete sparing of the lower lip. She denied pain but reported numbness of the upper lip. The patient visited her dentist who ruled out periodontal infection as the cause of the swelling. Diphenhydramine provided no relief; however, the cheek swelling resolved after a course of antibiotics prescribed by an ear, nose, and throat physician.

She consulted her primary care physician and was subsequently referred to a neurologist and allergist who were unable to provide a definitive diagnosis or complete relief of the symptoms. She denied any history of hypersensitivity reactions, odontogenic infections, gastrointestinal concerns, or any other signs or symptoms of systemic granulomatous disease.

Figure 1. Upper lip swelling without ulceration, fissuring, or scaling. The lower lip was completely spared.

On physical examination, the upper lip was swollen symmetrically without evidence of ulceration, fissuring, or scaling (Figure 1). Palpation of the upper lip was notable for firm, nontender, nonpitting edema without nodularity. The oral mucosa did not appear swollen or erythematous. Examination did not reveal ulceration or a cobblestone appearance.

A full-thickness skin biopsy of the upper lip was performed. Histopathology revealed perivascular nonnecrotizing granulomas adjacent to ectatic vascular channels with associated lymphoplasmacytic infiltrate (Figure 2). Periodic acid–Schiff stain was negative for fungal hyphae, tissue Gram stain was negative for bacteria, Fite and acid-fast bacillus stains were both negative for acid-fast organisms, and polariscopy was negative for polarizable foreign material. In this clinical context, the morphologic findings were consistent with the diagnosis of granulomatous cheilitis (GC).

Figure 2. Upper lip biopsy showed dermal edema, vascular ectasia, perivascular nonnecrotizing granulomas, and perivascular lymphocyte predominant inflammatory infiltrate (A)(H&E, original magnification ×100). Higher magnification of granulomas with perivascular lymphoplasmacytic infiltrate (B)(H&E, original magnification ×200).

Granulomatous cheilitis is a rare disorder of the lips and orofacial mucosa that was first described by Meischer¹ in 1945 as persistent or recurrent orofacial swelling secondary to lymphatic obstruction by granulomatous proliferation. It often has been described as a monosymptomatic form of Melkersson-Rosenthal syndrome (MRS). In its entirety, MRS constitutes a triad of GC, facial nerve palsy, and lingua plicata (also known as fissured tongue).^2,3 Although many authors agree that GC is associated with MRS, some believe that GC is a distinct entity because the majority of patients who present with GC subsequently do not develop MRS.⁴ Despite its relationship to MRS, the true incidence of GC largely is unknown. The onset of disease usually occurs in early adulthood but can present in middle-aged or older individuals.

The typical course of GC is relapsing and remitting, nontender and nonpitting swelling of the lips that eventually becomes permanent, leading to possible facial distortion and disability. Involvement of the upper lip is the most common, followed by (in order of decreasing frequency) the lower lip and cheeks.⁵ The swelling may be unilateral or bilateral and generally is not associated with ulceration, fissuring, or scaling; however, these complications have been reported in the terminal stages of the disease in which the macrocheilia has become permanent.

Despite the controversy over the etiology, pathophysiology, and classification of GC, it largely is accepted that when a patient presents clinically with a history of recurrent or persistent lip swelling, a 
full-thickness skin biopsy of the involved oral mucosa should be taken. Conditions that are considered in the differential diagnosis of orofacial granulomatosis are systemic granulomatous diseases that are known to have oral manifestations including Crohn disease, sarcoidosis, and mycobacterial infections. Given the many causes of orofacial and labial swelling, GC is a diagnosis of exclusion based on a thorough history and physical examination as well as appropriate diagnostic studies, with the cornerstone of the diagnosis resting on the histologic appearance of the lesion. Histologically, the diagnosis lies in the demonstration of granuloma formation, consisting of collections of epithelioid histiocytes and Langerhans giant cells. Once granuloma formation is documented, special stains are used to rule out other granulomatous diseases.

Intralesional steroids have been reported to provide the greatest improvement; however, in the majority of patients, multiple treatments are required.^6,7 Allen et al⁸ suggested that the efficacy of intralesional therapy increases when preceded by local anesthesia of the lip, thus allowing larger doses of triamcinolone to be tolerated by the patient. Systemic corticosteroids also have been used with moderate success, but the side effects of long-term systemic corticosteroid therapy make this treatment option less appealing.⁹ Other agents with known anti-inflammatory properties also have been used that may offer better side-effect profiles when used for long-term suppressive therapy, including 
clofazimine, dapsone, sulfapyridine, danazol, hydroxychloroquine, and antibiotics such as doxycycline and metronidazole.¹⁰

In severe or recalcitrant cases, surgical intervention by way of a reduction cheiloplasty is considered by some to be an appropriate next step in therapy but is rarely needed. Postoperative intralesional steroid injections are necessary due to reported cases of worsening disease when injections are discontinued after cheiloplasty.^11,12

Our patient was treated with 5 mg of intralesional triamcinolone acetonide with 10 separate injections of 0.5 cc each along the affected portions of the upper lip. She also was given doxycycline 100 mg once daily for 30 days. The patient reported complete resolution of the upper lip swelling 7 days after the initiation of therapy. At 1-month follow-up, she reported that the swelling had completely resolved. However, 1 day prior to the scheduled visit, shortly after finishing the course of doxycycline, she noted recurrent swelling. Due to the concomitant initial administration of both the steroid injections and doxycycline, it was unclear which treatment had provided relief. To avoid, or at least delay, the need for chronic intralesional steroid injections, another course of 40 mg doxycycline daily was prescribed. After 2 weeks, the patient reported that the swelling had markedly improved. The patient has 
maintained remission of the symptoms for approximately 6 months on daily suppressive therapy with 40 mg of doxycycline.

The recurrence of lip swelling after therapy, as in our patient, is typical of GC, and most cases require multiple follow-up visits and frequent alterations in therapy, which is often frustrating for both the patient and physician. However, awareness of this disease entity, its natural course, and the therapeutic options will allow physicians to more appropriately counsel and educate patients of this uncommon 
disease process.

To the Editor:

A 12-year-old girl presented with an asymptomatic hypopigmented area on the right cheek of 2 months’ duration. Two years prior to presentation she was diagnosed with neurofibromatosis type I (NF1) based on the findings of 13 café au lait spots on the trunk, axillary and groin freckling, bilateral Lisch nodules, and mild scoliosis. She was otherwise well and had no relevant medical history or family history of neurofibromatosis.

Physical examination revealed a 3×7-cm linear, shiny, sclerotic plaque extending from the right temple to the preauricular area and lower aspect of the right cheek (Figure 1) with associated facial asymmetry (Figure 2). A smaller similar plaque on the chin measured 0.5×0.5 cm. Examination of the oral cavity was unremarkable and there were no neurological signs. No other features were present to suggest a mixed connective tissue disease or lupus erythematosus, and nuclear antibodies were negative.

Figure 1. Linear sclerotic plaque extending from the right temple to the right preauricular area and right cheek.

Figure 2. Facial asymmetry with contraction of the right cheek.

An incisional biopsy from the sclerotic plaque revealed swollen eosinophilic bundles in the reticular dermis with a moderate perivascular lymphohistiocytic infiltrate extending into the subcutaneous layer. These features were compatible with the diagnosis of linear scleroderma. Due to the progressive nature of the condition and its anatomical location, she was treated with pulsed intravenous methylprednisolone 1 g daily for 3 days and commenced on oral methotrexate 20 mg weekly as well as tacrolimus ointment 0.1% daily. The plaque gradually softened and faded over a period of 8 months. The patient continued on methotrexate for another 10 months. The facial asymmetry persisted with a discernible reduction in the volume of the right cheek. New onset of ipsilateral jaw locking and pain associated with spasms of the muscles of mastication suggested the diagnosis of Parry-Romberg syndrome.

Neurofibromatosis type I is a neuroectodermal abnormality first described by Friedrich von Recklinghausen in 1882 with an incidence of 1 in 3000 births. Neurofibromatosis type I gene mutations lead to increased Ras activity, which is implicated in many NF1-related conditions such as neurofibromas and schwannomas.¹ Autoimmune conditions including systemic lupus erythematosus (SLE) and mixed connective tissue rarely have been reported in NF1, but the mechanism of their association is not clear.² Based on a review of 5 reported cases of NF1 and SLE, most patients were female, and the predominant features of NF1 were café au lait macules and neurofibromas.^3-6 One case documented a family history of NF1,⁶ suggesting predominance of sporadic mutations in these cases. Interestingly, in 3 cases the diagnosis of SLE preceded the diagnosis of NF1, prompting the authors to suggest a viral trigger for the development of NF1 lesions.^3,4 Linear scleroderma is immunologically mediated and is characterized by the onset of smooth indurated cutaneous plaques. According to a PubMed search of articles indexed for MEDLINE using the search terms morphea and neurofibromatosis as well as linear scleroderma and neurofibromatosis, there have been no reports of linear scleroderma or morphea associated with NF1. Cichowski et al⁷ demonstrated enhanced activation of Ras and prolonged activities of both Ras and extracellular signal-regulated kinase (ERK) signaling pathways in NF1-deficient mice. Chen et al⁸ showed that heparin sulfate–dependent ERK activation contributes to the development of scleroderma by promoting the expression of profibrotic proteins in scleroderma fibroblasts. It was previously noted that increased Ras/ERK signaling activities were important in connective tissue growth factor expression in normal mesenchymal cells.⁹

Based on these findings, we speculated that hyperactivation of Ras/ERK signaling from NF1 mutations could lead to the promotion of fibrosis seen in scleroderma. The lack of similar reports, however, suggests that the presence of both conditions in this case is coincidental. However, the growing number of reports on autoimmune and connective tissue disorders in NF1 reflects the need for further research in this area.

To the Editor:

A 12-year-old girl presented with an asymptomatic hypopigmented area on the right cheek of 2 months’ duration. Two years prior to presentation she was diagnosed with neurofibromatosis type I (NF1) based on the findings of 13 café au lait spots on the trunk, axillary and groin freckling, bilateral Lisch nodules, and mild scoliosis. She was otherwise well and had no relevant medical history or family history of neurofibromatosis.

Physical examination revealed a 3×7-cm linear, shiny, sclerotic plaque extending from the right temple to the preauricular area and lower aspect of the right cheek (Figure 1) with associated facial asymmetry (Figure 2). A smaller similar plaque on the chin measured 0.5×0.5 cm. Examination of the oral cavity was unremarkable and there were no neurological signs. No other features were present to suggest a mixed connective tissue disease or lupus erythematosus, and nuclear antibodies were negative.

Figure 1. Linear sclerotic plaque extending from the right temple to the right preauricular area and right cheek.

Figure 2. Facial asymmetry with contraction of the right cheek.

An incisional biopsy from the sclerotic plaque revealed swollen eosinophilic bundles in the reticular dermis with a moderate perivascular lymphohistiocytic infiltrate extending into the subcutaneous layer. These features were compatible with the diagnosis of linear scleroderma. Due to the progressive nature of the condition and its anatomical location, she was treated with pulsed intravenous methylprednisolone 1 g daily for 3 days and commenced on oral methotrexate 20 mg weekly as well as tacrolimus ointment 0.1% daily. The plaque gradually softened and faded over a period of 8 months. The patient continued on methotrexate for another 10 months. The facial asymmetry persisted with a discernible reduction in the volume of the right cheek. New onset of ipsilateral jaw locking and pain associated with spasms of the muscles of mastication suggested the diagnosis of Parry-Romberg syndrome.

Neurofibromatosis type I is a neuroectodermal abnormality first described by Friedrich von Recklinghausen in 1882 with an incidence of 1 in 3000 births. Neurofibromatosis type I gene mutations lead to increased Ras activity, which is implicated in many NF1-related conditions such as neurofibromas and schwannomas.¹ Autoimmune conditions including systemic lupus erythematosus (SLE) and mixed connective tissue rarely have been reported in NF1, but the mechanism of their association is not clear.² Based on a review of 5 reported cases of NF1 and SLE, most patients were female, and the predominant features of NF1 were café au lait macules and neurofibromas.^3-6 One case documented a family history of NF1,⁶ suggesting predominance of sporadic mutations in these cases. Interestingly, in 3 cases the diagnosis of SLE preceded the diagnosis of NF1, prompting the authors to suggest a viral trigger for the development of NF1 lesions.^3,4 Linear scleroderma is immunologically mediated and is characterized by the onset of smooth indurated cutaneous plaques. According to a PubMed search of articles indexed for MEDLINE using the search terms morphea and neurofibromatosis as well as linear scleroderma and neurofibromatosis, there have been no reports of linear scleroderma or morphea associated with NF1. Cichowski et al⁷ demonstrated enhanced activation of Ras and prolonged activities of both Ras and extracellular signal-regulated kinase (ERK) signaling pathways in NF1-deficient mice. Chen et al⁸ showed that heparin sulfate–dependent ERK activation contributes to the development of scleroderma by promoting the expression of profibrotic proteins in scleroderma fibroblasts. It was previously noted that increased Ras/ERK signaling activities were important in connective tissue growth factor expression in normal mesenchymal cells.⁹

Based on these findings, we speculated that hyperactivation of Ras/ERK signaling from NF1 mutations could lead to the promotion of fibrosis seen in scleroderma. The lack of similar reports, however, suggests that the presence of both conditions in this case is coincidental. However, the growing number of reports on autoimmune and connective tissue disorders in NF1 reflects the need for further research in this area.

To the Editor:

A 12-year-old girl presented with an asymptomatic hypopigmented area on the right cheek of 2 months’ duration. Two years prior to presentation she was diagnosed with neurofibromatosis type I (NF1) based on the findings of 13 café au lait spots on the trunk, axillary and groin freckling, bilateral Lisch nodules, and mild scoliosis. She was otherwise well and had no relevant medical history or family history of neurofibromatosis.

Physical examination revealed a 3×7-cm linear, shiny, sclerotic plaque extending from the right temple to the preauricular area and lower aspect of the right cheek (Figure 1) with associated facial asymmetry (Figure 2). A smaller similar plaque on the chin measured 0.5×0.5 cm. Examination of the oral cavity was unremarkable and there were no neurological signs. No other features were present to suggest a mixed connective tissue disease or lupus erythematosus, and nuclear antibodies were negative.

Figure 1. Linear sclerotic plaque extending from the right temple to the right preauricular area and right cheek.

Figure 2. Facial asymmetry with contraction of the right cheek.

An incisional biopsy from the sclerotic plaque revealed swollen eosinophilic bundles in the reticular dermis with a moderate perivascular lymphohistiocytic infiltrate extending into the subcutaneous layer. These features were compatible with the diagnosis of linear scleroderma. Due to the progressive nature of the condition and its anatomical location, she was treated with pulsed intravenous methylprednisolone 1 g daily for 3 days and commenced on oral methotrexate 20 mg weekly as well as tacrolimus ointment 0.1% daily. The plaque gradually softened and faded over a period of 8 months. The patient continued on methotrexate for another 10 months. The facial asymmetry persisted with a discernible reduction in the volume of the right cheek. New onset of ipsilateral jaw locking and pain associated with spasms of the muscles of mastication suggested the diagnosis of Parry-Romberg syndrome.

Neurofibromatosis type I is a neuroectodermal abnormality first described by Friedrich von Recklinghausen in 1882 with an incidence of 1 in 3000 births. Neurofibromatosis type I gene mutations lead to increased Ras activity, which is implicated in many NF1-related conditions such as neurofibromas and schwannomas.¹ Autoimmune conditions including systemic lupus erythematosus (SLE) and mixed connective tissue rarely have been reported in NF1, but the mechanism of their association is not clear.² Based on a review of 5 reported cases of NF1 and SLE, most patients were female, and the predominant features of NF1 were café au lait macules and neurofibromas.^3-6 One case documented a family history of NF1,⁶ suggesting predominance of sporadic mutations in these cases. Interestingly, in 3 cases the diagnosis of SLE preceded the diagnosis of NF1, prompting the authors to suggest a viral trigger for the development of NF1 lesions.^3,4 Linear scleroderma is immunologically mediated and is characterized by the onset of smooth indurated cutaneous plaques. According to a PubMed search of articles indexed for MEDLINE using the search terms morphea and neurofibromatosis as well as linear scleroderma and neurofibromatosis, there have been no reports of linear scleroderma or morphea associated with NF1. Cichowski et al⁷ demonstrated enhanced activation of Ras and prolonged activities of both Ras and extracellular signal-regulated kinase (ERK) signaling pathways in NF1-deficient mice. Chen et al⁸ showed that heparin sulfate–dependent ERK activation contributes to the development of scleroderma by promoting the expression of profibrotic proteins in scleroderma fibroblasts. It was previously noted that increased Ras/ERK signaling activities were important in connective tissue growth factor expression in normal mesenchymal cells.⁹

Based on these findings, we speculated that hyperactivation of Ras/ERK signaling from NF1 mutations could lead to the promotion of fibrosis seen in scleroderma. The lack of similar reports, however, suggests that the presence of both conditions in this case is coincidental. However, the growing number of reports on autoimmune and connective tissue disorders in NF1 reflects the need for further research in this area.

To the Editor:

A 38-year-old black man presented with a slowly enlarging growth on the left thigh of 7 years’ duration. The lesion would occasionally scrape off but always recurred. He reported that the tumor developed in the area of a prior nevus. He reported no direct trauma to the area, chronic inflammation, or similar lesions elsewhere. His medical history included gastroesophageal reflux disease and inactive sarcoidosis. Physical examination revealed a 3×3×1-cm exophytic, hyperkeratotic, erythematous nodule with surrounding stellate and branching hyperpigmentation on the anterior aspect of the thigh (Figure 1). Pathologic examination demonstrated hyperkeratosis with an endophytic proliferation of mildly atypical keratinocytes with broad blunted rete ridges (Figure 2). Complete excision of the lesion was performed.

Figure 1. An exophytic, hyperkeratotic, erythematous nodule with surrounding hyperpigmentation on the  anterior aspect of the left thigh.

A 33-year-old black man presented with a rapidly growing lesion on the right fifth toe of 3 months’ duration. The patient originally believed the initial small papule was a corn, and after attempts to shave it down with a razor blade, the lesion grew rapidly into a large painful tumor. He reported no prior trauma to the area or history of a similar lesion. Physical examination revealed a 2×2×0.5-cm hyperkeratotic, papillated, hard nodule with a heaped-up border and no ulceration or drainage (Figure 3). A shave biopsy of the lesion was obtained. Microscopic examination revealed hyperkeratosis, parakeratosis, and papillomatosis with deep extension of mildly atypical keratinocytes into the dermis. Small toe amputation was performed by an orthopedic surgeon.

Figure 2. Overall view of verrucous carcinoma on histology (A)(H&E, original magnification × A papillated endophytic proliferation of atypical keratinocytes of verrucous carcinoma was noted (B)(H&E, original magnification ×100).

Verrucous carcinoma, first described by Ackerman¹ in 1948, is an uncommon, low-grade, well-differentiated variant of squamous cell carcinoma. It presents as a slow-growing, bulky, exophytic tumor with a broad base. The tumor can ulcerate or present with surface sinus tracts that drain  foul-smelling material. Typically, the tumor occurs in the fifth to sixth decades of life, with men outnumbering women by a ratio of 5.3 to 1.2 The prevalence of verrucous carcinoma in black individuals is unknown. A review of nonmelanoma skin cancers in skin of color identifies squamous cell carcinoma as the most common cutaneous carcinoma but does not report on the rare verrucous variant.³

Figure 3. A hyperkeratotic, papillated, hard nodule with a rough surface on the right fifth toe.

Verrucous carcinoma is found in a variety of mucosal and skin surfaces. Verrucous carcinoma of the oral cavity, found most commonly on the buccal mucosa, is known as florid oral papillomatosis or Ackerman carcinoma. Cutaneous verrucous carcinoma is referred to as carcinoma cuniculatum or epithelioma cuniculatum and is predominantly located on the plantar surface of the foot. It is less commonly reported on the palm, scalp, face, extremities, and back. Verrucous carcinoma found in the anogenital area is referred to as the Buschke-Löwenstein tumor.⁴

Histologically, the lesion shows minimal cytologic atypia. Topped by an undulating keratinized mass, the deep margin of the tumor advances as a broad bulbous projection, compressing the underlying connective tissue in a bulldozing manner. Typically there also are keratin-filled sinuses and intraepidermal microabscesses.¹

Human papillomavirus types 6, 11, 16, and 18 may be involved in the induction of the tumor. Human papillomavirus types 6 and 11 are frequently associated with the Buschke-Löwenstein tumor,^2,4 while carcinoma cuniculatum is most commonly associated with human papillomavirus 16.^5-7 In several cases of verrucous carcinoma, the tumor was reported to arise from preexisting lesions with chronic inflammation, such as a chronic ulcer, inflamed cyst, or burn scar.² Ackerman carcinoma has been associated with the use of snuff, chewing tobacco, and betel nuts.

Morbidity and mortality from verrucous carcinoma arises from local invasion and infiltration into adjacent bone. The tumor rarely metastasizes, with regional lymph nodes being the only reported site of metastasis.⁸ The treatment of cutaneous verrucous carcinoma is complete surgical excision. Mohs micrographic surgery is preferred because it minimizes recurrence risk.⁴ Radiation therapy is contraindicated because it has been reported to cause the tumor to become more aggressive.^9,10 Although local recurrence may occur, the prognosis is usually favorable.

To the Editor:

A 38-year-old black man presented with a slowly enlarging growth on the left thigh of 7 years’ duration. The lesion would occasionally scrape off but always recurred. He reported that the tumor developed in the area of a prior nevus. He reported no direct trauma to the area, chronic inflammation, or similar lesions elsewhere. His medical history included gastroesophageal reflux disease and inactive sarcoidosis. Physical examination revealed a 3×3×1-cm exophytic, hyperkeratotic, erythematous nodule with surrounding stellate and branching hyperpigmentation on the anterior aspect of the thigh (Figure 1). Pathologic examination demonstrated hyperkeratosis with an endophytic proliferation of mildly atypical keratinocytes with broad blunted rete ridges (Figure 2). Complete excision of the lesion was performed.

Figure 1. An exophytic, hyperkeratotic, erythematous nodule with surrounding hyperpigmentation on the  anterior aspect of the left thigh.

A 33-year-old black man presented with a rapidly growing lesion on the right fifth toe of 3 months’ duration. The patient originally believed the initial small papule was a corn, and after attempts to shave it down with a razor blade, the lesion grew rapidly into a large painful tumor. He reported no prior trauma to the area or history of a similar lesion. Physical examination revealed a 2×2×0.5-cm hyperkeratotic, papillated, hard nodule with a heaped-up border and no ulceration or drainage (Figure 3). A shave biopsy of the lesion was obtained. Microscopic examination revealed hyperkeratosis, parakeratosis, and papillomatosis with deep extension of mildly atypical keratinocytes into the dermis. Small toe amputation was performed by an orthopedic surgeon.

Figure 2. Overall view of verrucous carcinoma on histology (A)(H&E, original magnification × A papillated endophytic proliferation of atypical keratinocytes of verrucous carcinoma was noted (B)(H&E, original magnification ×100).

Verrucous carcinoma, first described by Ackerman¹ in 1948, is an uncommon, low-grade, well-differentiated variant of squamous cell carcinoma. It presents as a slow-growing, bulky, exophytic tumor with a broad base. The tumor can ulcerate or present with surface sinus tracts that drain  foul-smelling material. Typically, the tumor occurs in the fifth to sixth decades of life, with men outnumbering women by a ratio of 5.3 to 1.2 The prevalence of verrucous carcinoma in black individuals is unknown. A review of nonmelanoma skin cancers in skin of color identifies squamous cell carcinoma as the most common cutaneous carcinoma but does not report on the rare verrucous variant.³

Figure 3. A hyperkeratotic, papillated, hard nodule with a rough surface on the right fifth toe.

Verrucous carcinoma is found in a variety of mucosal and skin surfaces. Verrucous carcinoma of the oral cavity, found most commonly on the buccal mucosa, is known as florid oral papillomatosis or Ackerman carcinoma. Cutaneous verrucous carcinoma is referred to as carcinoma cuniculatum or epithelioma cuniculatum and is predominantly located on the plantar surface of the foot. It is less commonly reported on the palm, scalp, face, extremities, and back. Verrucous carcinoma found in the anogenital area is referred to as the Buschke-Löwenstein tumor.⁴

Histologically, the lesion shows minimal cytologic atypia. Topped by an undulating keratinized mass, the deep margin of the tumor advances as a broad bulbous projection, compressing the underlying connective tissue in a bulldozing manner. Typically there also are keratin-filled sinuses and intraepidermal microabscesses.¹

Human papillomavirus types 6, 11, 16, and 18 may be involved in the induction of the tumor. Human papillomavirus types 6 and 11 are frequently associated with the Buschke-Löwenstein tumor,^2,4 while carcinoma cuniculatum is most commonly associated with human papillomavirus 16.^5-7 In several cases of verrucous carcinoma, the tumor was reported to arise from preexisting lesions with chronic inflammation, such as a chronic ulcer, inflamed cyst, or burn scar.² Ackerman carcinoma has been associated with the use of snuff, chewing tobacco, and betel nuts.

Morbidity and mortality from verrucous carcinoma arises from local invasion and infiltration into adjacent bone. The tumor rarely metastasizes, with regional lymph nodes being the only reported site of metastasis.⁸ The treatment of cutaneous verrucous carcinoma is complete surgical excision. Mohs micrographic surgery is preferred because it minimizes recurrence risk.⁴ Radiation therapy is contraindicated because it has been reported to cause the tumor to become more aggressive.^9,10 Although local recurrence may occur, the prognosis is usually favorable.

To the Editor:

A 38-year-old black man presented with a slowly enlarging growth on the left thigh of 7 years’ duration. The lesion would occasionally scrape off but always recurred. He reported that the tumor developed in the area of a prior nevus. He reported no direct trauma to the area, chronic inflammation, or similar lesions elsewhere. His medical history included gastroesophageal reflux disease and inactive sarcoidosis. Physical examination revealed a 3×3×1-cm exophytic, hyperkeratotic, erythematous nodule with surrounding stellate and branching hyperpigmentation on the anterior aspect of the thigh (Figure 1). Pathologic examination demonstrated hyperkeratosis with an endophytic proliferation of mildly atypical keratinocytes with broad blunted rete ridges (Figure 2). Complete excision of the lesion was performed.

Figure 1. An exophytic, hyperkeratotic, erythematous nodule with surrounding hyperpigmentation on the  anterior aspect of the left thigh.

A 33-year-old black man presented with a rapidly growing lesion on the right fifth toe of 3 months’ duration. The patient originally believed the initial small papule was a corn, and after attempts to shave it down with a razor blade, the lesion grew rapidly into a large painful tumor. He reported no prior trauma to the area or history of a similar lesion. Physical examination revealed a 2×2×0.5-cm hyperkeratotic, papillated, hard nodule with a heaped-up border and no ulceration or drainage (Figure 3). A shave biopsy of the lesion was obtained. Microscopic examination revealed hyperkeratosis, parakeratosis, and papillomatosis with deep extension of mildly atypical keratinocytes into the dermis. Small toe amputation was performed by an orthopedic surgeon.

Figure 2. Overall view of verrucous carcinoma on histology (A)(H&E, original magnification × A papillated endophytic proliferation of atypical keratinocytes of verrucous carcinoma was noted (B)(H&E, original magnification ×100).

Verrucous carcinoma, first described by Ackerman¹ in 1948, is an uncommon, low-grade, well-differentiated variant of squamous cell carcinoma. It presents as a slow-growing, bulky, exophytic tumor with a broad base. The tumor can ulcerate or present with surface sinus tracts that drain  foul-smelling material. Typically, the tumor occurs in the fifth to sixth decades of life, with men outnumbering women by a ratio of 5.3 to 1.2 The prevalence of verrucous carcinoma in black individuals is unknown. A review of nonmelanoma skin cancers in skin of color identifies squamous cell carcinoma as the most common cutaneous carcinoma but does not report on the rare verrucous variant.³

Figure 3. A hyperkeratotic, papillated, hard nodule with a rough surface on the right fifth toe.

Verrucous carcinoma is found in a variety of mucosal and skin surfaces. Verrucous carcinoma of the oral cavity, found most commonly on the buccal mucosa, is known as florid oral papillomatosis or Ackerman carcinoma. Cutaneous verrucous carcinoma is referred to as carcinoma cuniculatum or epithelioma cuniculatum and is predominantly located on the plantar surface of the foot. It is less commonly reported on the palm, scalp, face, extremities, and back. Verrucous carcinoma found in the anogenital area is referred to as the Buschke-Löwenstein tumor.⁴

Histologically, the lesion shows minimal cytologic atypia. Topped by an undulating keratinized mass, the deep margin of the tumor advances as a broad bulbous projection, compressing the underlying connective tissue in a bulldozing manner. Typically there also are keratin-filled sinuses and intraepidermal microabscesses.¹

Human papillomavirus types 6, 11, 16, and 18 may be involved in the induction of the tumor. Human papillomavirus types 6 and 11 are frequently associated with the Buschke-Löwenstein tumor,^2,4 while carcinoma cuniculatum is most commonly associated with human papillomavirus 16.^5-7 In several cases of verrucous carcinoma, the tumor was reported to arise from preexisting lesions with chronic inflammation, such as a chronic ulcer, inflamed cyst, or burn scar.² Ackerman carcinoma has been associated with the use of snuff, chewing tobacco, and betel nuts.

Morbidity and mortality from verrucous carcinoma arises from local invasion and infiltration into adjacent bone. The tumor rarely metastasizes, with regional lymph nodes being the only reported site of metastasis.⁸ The treatment of cutaneous verrucous carcinoma is complete surgical excision. Mohs micrographic surgery is preferred because it minimizes recurrence risk.⁴ Radiation therapy is contraindicated because it has been reported to cause the tumor to become more aggressive.^9,10 Although local recurrence may occur, the prognosis is usually favorable.

To the Editor:

Sweet syndrome is a neutrophilic dermatosis that typically presents as an acute onset of multiple, painful, sharply demarcated, small (measuring a few centimeters), raised, red plaques that occasionally present with superimposed pustules, vesicles, or bullae on the face, neck, upper chest, back, and extremities. Patients are often febrile and may have mucosal and systemic involvement.¹ Although 71% of cases are idiopathic, others are associated with malignancy; autoimmune disorders; infections; pregnancy; and rarely medications, especially all-trans-retinoic acid, granulocyte colony-stimulating factor, vaccines, and antibiotics.^1,2 We present a case of Sweet syndrome induced by trimethoprim-sulfamethoxazole (TMP-SMX) with an unusual clinical presentation.

A 71-year-old man with a medical history of nonmelanoma skin cancer initiated a course of  TMP-SMX for a wound infection of the lower leg following Mohs micrographic surgery. Eight days later, he developed a painful eruption preceded by 1 day of fever, malaise, blurry vision, and myalgia. Trimethoprim-sulfamethoxazole was discontinued. Physical examination revealed ill-defined, discrete and coalescing, 1- to 6-mm edematous erythematous papules studded with pustules involving the scalp, face, neck, back (Figure 1), and extremities. The patient also had conjunctival erythema and an elevated temperature (38.3°C). Laboratory workup revealed an elevated white blood cell count (11,300/mL [reference range, 4500–11,000/µL]), blood urea nitrogen level (33 mg/µL [reference range, 7–20 mg/dL]),  and creatinine level (2.00 mg/dL [reference range,  0.6–1.2 mg/dL]). Liver function tests were normal. A biopsy demonstrated marked papillary dermal edema with a dense, bandlike, superficial dermal neutrophilic infiltrate (Figure 2). A few neutrophils were present in the epidermis with formation of minute intraepidermal pustules. The patient was diagnosed with Sweet syndrome and treated with intravenous methylprednisolone 60 mg 3 times daily (1.5 mg/kg body weight) tapered over 17 days and triamcinolone acetonide ointment 0.1% twice daily. His fever and leukocytosis resolved within 1 day and the eruption improved within 2 days with residual desquamation that cleared by 3 weeks.

Figure 1. Ill-defined, discrete and coalescing, 1- to 6-mm erythematous papules studded with pustules on the back.

Figure 2. Marked papillary dermal edema, a dense superficial dermal neutrophilic infiltrate, and neutrophil exocytosis with formation of minute intraepidermal pustules (H&E, original magnification ×200).

Morphologically, our case resembled acute generalized exanthematous pustulosis (AGEP), which presents with edematous erythema studded with pustules.³ Although fever and leukocytosis are often present in both AGEP and Sweet syndrome, our patient’s pain, malaise, and myalgia favored Sweet syndrome, as did his conjunctivitis, which is unusual in AGEP.^1,3 Histologically, our case was characteristic for Sweet syndrome, which presents with marked papillary dermal edema and a dense neutrophilic dermal infiltrate with neutrophil exocytosis and spongiform pustules in 21% of cases.¹ Acute generalized exanthematous pustulosis, characterized by spongiform pustules and a perivascular neutrophilic infiltrate, does not exhibit the dense dermal neutrophilic infiltrate of Sweet syndrome.³  Mecca et al⁴ also reported a case displaying overlapping features of Sweet syndrome and AGEP. The patient presented with photodistributed papules and pinpoint pustules on an erythematous base favoring a diagnosis of AGEP with histologic findings compatible with Sweet syndrome. The authors suggested a clinicopathologic continuum may exist among drug-related neutrophilic dermatoses.⁴

In conclusion, we present a case of TMP-SMX–induced Sweet syndrome that morphologically resembled AGEP. It is important to recognize that Sweet syndrome may present in this unusual manner, as it may have notable internal involvement, and responds rapidly to systemic steroids, whereas AGEP has minimal systemic involvement and clears spontaneously.

To the Editor:

Sweet syndrome is a neutrophilic dermatosis that typically presents as an acute onset of multiple, painful, sharply demarcated, small (measuring a few centimeters), raised, red plaques that occasionally present with superimposed pustules, vesicles, or bullae on the face, neck, upper chest, back, and extremities. Patients are often febrile and may have mucosal and systemic involvement.¹ Although 71% of cases are idiopathic, others are associated with malignancy; autoimmune disorders; infections; pregnancy; and rarely medications, especially all-trans-retinoic acid, granulocyte colony-stimulating factor, vaccines, and antibiotics.^1,2 We present a case of Sweet syndrome induced by trimethoprim-sulfamethoxazole (TMP-SMX) with an unusual clinical presentation.

A 71-year-old man with a medical history of nonmelanoma skin cancer initiated a course of  TMP-SMX for a wound infection of the lower leg following Mohs micrographic surgery. Eight days later, he developed a painful eruption preceded by 1 day of fever, malaise, blurry vision, and myalgia. Trimethoprim-sulfamethoxazole was discontinued. Physical examination revealed ill-defined, discrete and coalescing, 1- to 6-mm edematous erythematous papules studded with pustules involving the scalp, face, neck, back (Figure 1), and extremities. The patient also had conjunctival erythema and an elevated temperature (38.3°C). Laboratory workup revealed an elevated white blood cell count (11,300/mL [reference range, 4500–11,000/µL]), blood urea nitrogen level (33 mg/µL [reference range, 7–20 mg/dL]),  and creatinine level (2.00 mg/dL [reference range,  0.6–1.2 mg/dL]). Liver function tests were normal. A biopsy demonstrated marked papillary dermal edema with a dense, bandlike, superficial dermal neutrophilic infiltrate (Figure 2). A few neutrophils were present in the epidermis with formation of minute intraepidermal pustules. The patient was diagnosed with Sweet syndrome and treated with intravenous methylprednisolone 60 mg 3 times daily (1.5 mg/kg body weight) tapered over 17 days and triamcinolone acetonide ointment 0.1% twice daily. His fever and leukocytosis resolved within 1 day and the eruption improved within 2 days with residual desquamation that cleared by 3 weeks.

Figure 1. Ill-defined, discrete and coalescing, 1- to 6-mm erythematous papules studded with pustules on the back.

Figure 2. Marked papillary dermal edema, a dense superficial dermal neutrophilic infiltrate, and neutrophil exocytosis with formation of minute intraepidermal pustules (H&E, original magnification ×200).

Morphologically, our case resembled acute generalized exanthematous pustulosis (AGEP), which presents with edematous erythema studded with pustules.³ Although fever and leukocytosis are often present in both AGEP and Sweet syndrome, our patient’s pain, malaise, and myalgia favored Sweet syndrome, as did his conjunctivitis, which is unusual in AGEP.^1,3 Histologically, our case was characteristic for Sweet syndrome, which presents with marked papillary dermal edema and a dense neutrophilic dermal infiltrate with neutrophil exocytosis and spongiform pustules in 21% of cases.¹ Acute generalized exanthematous pustulosis, characterized by spongiform pustules and a perivascular neutrophilic infiltrate, does not exhibit the dense dermal neutrophilic infiltrate of Sweet syndrome.³  Mecca et al⁴ also reported a case displaying overlapping features of Sweet syndrome and AGEP. The patient presented with photodistributed papules and pinpoint pustules on an erythematous base favoring a diagnosis of AGEP with histologic findings compatible with Sweet syndrome. The authors suggested a clinicopathologic continuum may exist among drug-related neutrophilic dermatoses.⁴

In conclusion, we present a case of TMP-SMX–induced Sweet syndrome that morphologically resembled AGEP. It is important to recognize that Sweet syndrome may present in this unusual manner, as it may have notable internal involvement, and responds rapidly to systemic steroids, whereas AGEP has minimal systemic involvement and clears spontaneously.

To the Editor:

Sweet syndrome is a neutrophilic dermatosis that typically presents as an acute onset of multiple, painful, sharply demarcated, small (measuring a few centimeters), raised, red plaques that occasionally present with superimposed pustules, vesicles, or bullae on the face, neck, upper chest, back, and extremities. Patients are often febrile and may have mucosal and systemic involvement.¹ Although 71% of cases are idiopathic, others are associated with malignancy; autoimmune disorders; infections; pregnancy; and rarely medications, especially all-trans-retinoic acid, granulocyte colony-stimulating factor, vaccines, and antibiotics.^1,2 We present a case of Sweet syndrome induced by trimethoprim-sulfamethoxazole (TMP-SMX) with an unusual clinical presentation.

A 71-year-old man with a medical history of nonmelanoma skin cancer initiated a course of  TMP-SMX for a wound infection of the lower leg following Mohs micrographic surgery. Eight days later, he developed a painful eruption preceded by 1 day of fever, malaise, blurry vision, and myalgia. Trimethoprim-sulfamethoxazole was discontinued. Physical examination revealed ill-defined, discrete and coalescing, 1- to 6-mm edematous erythematous papules studded with pustules involving the scalp, face, neck, back (Figure 1), and extremities. The patient also had conjunctival erythema and an elevated temperature (38.3°C). Laboratory workup revealed an elevated white blood cell count (11,300/mL [reference range, 4500–11,000/µL]), blood urea nitrogen level (33 mg/µL [reference range, 7–20 mg/dL]),  and creatinine level (2.00 mg/dL [reference range,  0.6–1.2 mg/dL]). Liver function tests were normal. A biopsy demonstrated marked papillary dermal edema with a dense, bandlike, superficial dermal neutrophilic infiltrate (Figure 2). A few neutrophils were present in the epidermis with formation of minute intraepidermal pustules. The patient was diagnosed with Sweet syndrome and treated with intravenous methylprednisolone 60 mg 3 times daily (1.5 mg/kg body weight) tapered over 17 days and triamcinolone acetonide ointment 0.1% twice daily. His fever and leukocytosis resolved within 1 day and the eruption improved within 2 days with residual desquamation that cleared by 3 weeks.

Figure 1. Ill-defined, discrete and coalescing, 1- to 6-mm erythematous papules studded with pustules on the back.

Figure 2. Marked papillary dermal edema, a dense superficial dermal neutrophilic infiltrate, and neutrophil exocytosis with formation of minute intraepidermal pustules (H&E, original magnification ×200).

Morphologically, our case resembled acute generalized exanthematous pustulosis (AGEP), which presents with edematous erythema studded with pustules.³ Although fever and leukocytosis are often present in both AGEP and Sweet syndrome, our patient’s pain, malaise, and myalgia favored Sweet syndrome, as did his conjunctivitis, which is unusual in AGEP.^1,3 Histologically, our case was characteristic for Sweet syndrome, which presents with marked papillary dermal edema and a dense neutrophilic dermal infiltrate with neutrophil exocytosis and spongiform pustules in 21% of cases.¹ Acute generalized exanthematous pustulosis, characterized by spongiform pustules and a perivascular neutrophilic infiltrate, does not exhibit the dense dermal neutrophilic infiltrate of Sweet syndrome.³  Mecca et al⁴ also reported a case displaying overlapping features of Sweet syndrome and AGEP. The patient presented with photodistributed papules and pinpoint pustules on an erythematous base favoring a diagnosis of AGEP with histologic findings compatible with Sweet syndrome. The authors suggested a clinicopathologic continuum may exist among drug-related neutrophilic dermatoses.⁴

In conclusion, we present a case of TMP-SMX–induced Sweet syndrome that morphologically resembled AGEP. It is important to recognize that Sweet syndrome may present in this unusual manner, as it may have notable internal involvement, and responds rapidly to systemic steroids, whereas AGEP has minimal systemic involvement and clears spontaneously.

To the Editor:

A 66-year-old man with hypertension presented with asymptomatic, edematous, swelling plaques without local heat on the bilateral auricles of 2 months’ duration (Figure 1). Topical corticosteroids and multiple oral antihistamines were prescribed without any improvement. He reported no history of trauma or use of any topical agents except topical corticosteroids. There was no sensory defect or numbness.

Figure 1. Asymptomatic, edematous, swelling and indurated plaques without local heat on the bilateral auricles (A and B).

Laboratory results revealed leukocytosis with a white blood cell count of 13,900/mL (reference range, 3500–9900/μL) and 55.8% lymphocytes (reference range, 20%–40%). Biochemistry and tumor markers data were normal. No palpable neck lymphadenopathy was found. A skin biopsy was performed on the left earlobe showing a grenz zone between the tumor infiltrate and epidermis and a dense neoplastic lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (Figure 2A). These lymphoid cells were small to medium sized with indented and irregular nuclei and abundant pale cytoplasm (Figure 2B). Immunohistochemical staining showed positivity for CD20 and BCL2; stains for CD5, CD10, CD23, and BCL6 were negative. Positron emission tomography scan showed bilateral auricular infiltration and bilateral neck lymph node involvement. A bone marrow biopsy was performed during hospitalization and was positive for lymphoma involvement. On the basis of histologic and immunohistochemical findings, a diagnosis of malignant nodal marginal zone lymphoma (MZL) with cutaneous involvement was made. The patient underwent chemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

Figure 2. A skin biopsy showed basket weave hyperkeratosis, a grenz zone between the tumor infiltrate and epidermis, and dense lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (A)(H&E, original magnification ×40). Small- to medium-sized lymphoid cells with indented and irregular nuclei and abundant pale cytoplasm were seen (B)(H&E, original magnification ×400).

Cutaneous MZL may be a primary cutaneous condition or the result of secondary involvement from noncutaneous MZL. The histologic and immunophenotypic changes in skin lesions from secondary cutaneous MZL may be indistinguishable from those in primary cutaneous MZL. Primary cutaneous MZL may be seen in younger patients and favors the trunk and extremities, whereas MZL secondarily involves the skin, favors the head and neck regions, and is limited to older patients.¹ Histologic aspects include a dense, nodular, deep-seated infiltrate containing various proportions of small cells displaying a centrocytelike, plasmacytoid, or monocytoid appearance.² Chronic antigen stimulation is a key player in the pathogenesis and involves deregulation of the nuclear factor κb pathway. While Helicobacter pylori and Epstein-Barr virus do not seem to be implicated in primary cutaneous MZL, the role of Borrelia burgdorferi is still a matter of debate with discordant results.^3,4

Treatment may include excision, curative or adjunctive radiotherapy, topical or intralesional corticosteroids, interferon or intralesional rituximab, or systemic therapies such as chemotherapy and/or intravenous rituximab depending on disease stage and tumor burden.⁵

Cutaneous presentation of MZL as bilateral auricular swelling is unique. Because there may be considerable overlap in the clinical presentations for patients with primary and secondary cutaneous MZL, it is imperative to perform a systemic evaluation. Clinicians should be aware of possible hematologic malignancy in patients with unexplained and refractory bilateral auricular swelling.

To the Editor:

A 66-year-old man with hypertension presented with asymptomatic, edematous, swelling plaques without local heat on the bilateral auricles of 2 months’ duration (Figure 1). Topical corticosteroids and multiple oral antihistamines were prescribed without any improvement. He reported no history of trauma or use of any topical agents except topical corticosteroids. There was no sensory defect or numbness.

Figure 1. Asymptomatic, edematous, swelling and indurated plaques without local heat on the bilateral auricles (A and B).

Laboratory results revealed leukocytosis with a white blood cell count of 13,900/mL (reference range, 3500–9900/μL) and 55.8% lymphocytes (reference range, 20%–40%). Biochemistry and tumor markers data were normal. No palpable neck lymphadenopathy was found. A skin biopsy was performed on the left earlobe showing a grenz zone between the tumor infiltrate and epidermis and a dense neoplastic lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (Figure 2A). These lymphoid cells were small to medium sized with indented and irregular nuclei and abundant pale cytoplasm (Figure 2B). Immunohistochemical staining showed positivity for CD20 and BCL2; stains for CD5, CD10, CD23, and BCL6 were negative. Positron emission tomography scan showed bilateral auricular infiltration and bilateral neck lymph node involvement. A bone marrow biopsy was performed during hospitalization and was positive for lymphoma involvement. On the basis of histologic and immunohistochemical findings, a diagnosis of malignant nodal marginal zone lymphoma (MZL) with cutaneous involvement was made. The patient underwent chemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

Figure 2. A skin biopsy showed basket weave hyperkeratosis, a grenz zone between the tumor infiltrate and epidermis, and dense lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (A)(H&E, original magnification ×40). Small- to medium-sized lymphoid cells with indented and irregular nuclei and abundant pale cytoplasm were seen (B)(H&E, original magnification ×400).

Cutaneous MZL may be a primary cutaneous condition or the result of secondary involvement from noncutaneous MZL. The histologic and immunophenotypic changes in skin lesions from secondary cutaneous MZL may be indistinguishable from those in primary cutaneous MZL. Primary cutaneous MZL may be seen in younger patients and favors the trunk and extremities, whereas MZL secondarily involves the skin, favors the head and neck regions, and is limited to older patients.¹ Histologic aspects include a dense, nodular, deep-seated infiltrate containing various proportions of small cells displaying a centrocytelike, plasmacytoid, or monocytoid appearance.² Chronic antigen stimulation is a key player in the pathogenesis and involves deregulation of the nuclear factor κb pathway. While Helicobacter pylori and Epstein-Barr virus do not seem to be implicated in primary cutaneous MZL, the role of Borrelia burgdorferi is still a matter of debate with discordant results.^3,4

Treatment may include excision, curative or adjunctive radiotherapy, topical or intralesional corticosteroids, interferon or intralesional rituximab, or systemic therapies such as chemotherapy and/or intravenous rituximab depending on disease stage and tumor burden.⁵

Cutaneous presentation of MZL as bilateral auricular swelling is unique. Because there may be considerable overlap in the clinical presentations for patients with primary and secondary cutaneous MZL, it is imperative to perform a systemic evaluation. Clinicians should be aware of possible hematologic malignancy in patients with unexplained and refractory bilateral auricular swelling.

To the Editor:

A 66-year-old man with hypertension presented with asymptomatic, edematous, swelling plaques without local heat on the bilateral auricles of 2 months’ duration (Figure 1). Topical corticosteroids and multiple oral antihistamines were prescribed without any improvement. He reported no history of trauma or use of any topical agents except topical corticosteroids. There was no sensory defect or numbness.

Figure 1. Asymptomatic, edematous, swelling and indurated plaques without local heat on the bilateral auricles (A and B).

Laboratory results revealed leukocytosis with a white blood cell count of 13,900/mL (reference range, 3500–9900/μL) and 55.8% lymphocytes (reference range, 20%–40%). Biochemistry and tumor markers data were normal. No palpable neck lymphadenopathy was found. A skin biopsy was performed on the left earlobe showing a grenz zone between the tumor infiltrate and epidermis and a dense neoplastic lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (Figure 2A). These lymphoid cells were small to medium sized with indented and irregular nuclei and abundant pale cytoplasm (Figure 2B). Immunohistochemical staining showed positivity for CD20 and BCL2; stains for CD5, CD10, CD23, and BCL6 were negative. Positron emission tomography scan showed bilateral auricular infiltration and bilateral neck lymph node involvement. A bone marrow biopsy was performed during hospitalization and was positive for lymphoma involvement. On the basis of histologic and immunohistochemical findings, a diagnosis of malignant nodal marginal zone lymphoma (MZL) with cutaneous involvement was made. The patient underwent chemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

Figure 2. A skin biopsy showed basket weave hyperkeratosis, a grenz zone between the tumor infiltrate and epidermis, and dense lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (A)(H&E, original magnification ×40). Small- to medium-sized lymphoid cells with indented and irregular nuclei and abundant pale cytoplasm were seen (B)(H&E, original magnification ×400).

Cutaneous MZL may be a primary cutaneous condition or the result of secondary involvement from noncutaneous MZL. The histologic and immunophenotypic changes in skin lesions from secondary cutaneous MZL may be indistinguishable from those in primary cutaneous MZL. Primary cutaneous MZL may be seen in younger patients and favors the trunk and extremities, whereas MZL secondarily involves the skin, favors the head and neck regions, and is limited to older patients.¹ Histologic aspects include a dense, nodular, deep-seated infiltrate containing various proportions of small cells displaying a centrocytelike, plasmacytoid, or monocytoid appearance.² Chronic antigen stimulation is a key player in the pathogenesis and involves deregulation of the nuclear factor κb pathway. While Helicobacter pylori and Epstein-Barr virus do not seem to be implicated in primary cutaneous MZL, the role of Borrelia burgdorferi is still a matter of debate with discordant results.^3,4

Treatment may include excision, curative or adjunctive radiotherapy, topical or intralesional corticosteroids, interferon or intralesional rituximab, or systemic therapies such as chemotherapy and/or intravenous rituximab depending on disease stage and tumor burden.⁵

Cutaneous presentation of MZL as bilateral auricular swelling is unique. Because there may be considerable overlap in the clinical presentations for patients with primary and secondary cutaneous MZL, it is imperative to perform a systemic evaluation. Clinicians should be aware of possible hematologic malignancy in patients with unexplained and refractory bilateral auricular swelling.